Pharmaceutical composition, methods for treating and uses thereof

ABSTRACT

The present invention relates to certain SGLT-2 inhibitors for treating and/or preventing oxidative stress, for example in patients with type 1 or type 2 diabetes, as well as to the use of such SGLT-2 inhibitors in treatment and/or prevention of cardiovascular diseases in patients, for example type 1 or type 2 diabetes patients. The present invention further relates to certain SGLT-2 inhibitors for treating and/or preventing a metabolic disorder and preventing, reducing the risk of or delaying the occurrence of a cardiovascular event in patients, for example patients with type 1 or type 2 diabetes.

TECHNICAL FIELD OF THE INVENTION

The present invention relates to certain SGLT-2 inhibitors for treatingand/or preventing oxidative stress, for example in patients with type 1or type 2 diabetes mellitus, as well as to the use of such SGLT-2inhibitors in treatment and/or prevention of cardiovascular diseases inpatients, for example type 1 or type 2 diabetes mellitus patients. Thepresent invention further relates to certain SGLT-2 inhibitors fortreating and/or preventing a metabolic disorder and preventing, reducingthe risk of or delaying the occurrence of a cardiovascular event inpatients, for example patients with type 1 or type 2 diabetes mellitus.

BACKGROUND OF THE INVENTION

The rising prevalences of type 2 diabetes mellitus (T2DM) representmajor challenges for global public health. Worldwide, there are morethan 220 million patients with type 2 diabetes mellitus, figures whichare projected to rise by 2030 (World Health Organisation 2010;International Diabetes Federation 2010). According to the US Centers forDisease Control and Prevention, rates of type 2 diabetes mellitus havetripled in the past 30 years. Diabetes now affects an estimated 23.6million people in the United States; another 57 million haveprediabetes. Prediabetes raises short-term absolute risk of type 2diabetes mellitus five- to sixfold.

Type 2 diabetes mellitus is an increasingly prevalent disease that dueto a high frequency of complications leads to a significant reduction oflife expectancy. Because of diabetes-associated microvascularcomplications, type 2 diabetes is currently the most frequent cause ofadult-onset loss of vision, renal failure, and amputations in theindustrialized world. In addition, the presence of type 2 diabetesmellitus is associated with a two to five fold increase incardiovascular disease risk.

After long duration of disease, most patients with type 2 diabetesmellitus will eventually fail on oral therapy and become insulindependent with the necessity for daily injections and multiple dailyglucose measurements.

The UKPDS (United Kingdom Prospective Diabetes Study) demonstrated thatintensive treatment with metformin, sulfonylureas or insulin resulted inonly a limited improvement of glycemic control (difference in HbA1c˜0.9%). In addition, even in patients within the intensive treatment armglycemic control deteriorated significantly over time and this wasattributed to deterioration of β-cell function. Therefore many patientswith type 2 diabetes mellitus remain inadequately treated, partlybecause of limitations in long term efficacy, tolerability and dosinginconvenience of existing antihyperglycemic therapies.

Oral antidiabetic drugs conventionally used in therapy (such as e.g.first- or second-line, and/or mono- or (initial or add-on) combinationtherapy) include, without being restricted thereto, metformin,sulphonylureas, thiazolidinediones, glinides, DPP-4 inhibitors andα-glucosidase inhibitors.

The high incidence of therapeutic failure is a major contributor to thehigh rate of long-term hyperglycemia-associated complications or chronicdamages (including micro- and macrovascular complications such as e.g.diabetic nephrophathy, retinopathy or neuropathy, or cardiovascularcomplications) in patients with type 2 diabetes mellitus.

Therefore, there is an unmet medical need for methods, medicaments andpharmaceutical compositions with a good efficacy with regard to glycemiccontrol, with regard to disease-modifying properties and with regard toreduction of cardiovascular morbidity and mortality while at the sametime showing an improved safety profile.

SUMMARY OF THE INVENTION

The present invention relates to certain SGLT-2 inhibitors for treatingand/or preventing oxidative stress, for example in patients with type 1or type 2 diabetes mellitus. The present invention also relates to theuse of such SGLT-2 inhibitors in the treatment and/or prevention ofcardiovascular diseases in patients, for example in type 1 or type 2diabetes mellitus patients. The present invention also relates to theuse of such SGLT-2 inhibitors in treatment and/or prevention of ametabolic disorder in patients with or at risk of cardiovasculardisease. The present invention further relates to certain SGLT-2inhibitors for treating and/or preventing a metabolic disorder andpreventing, reducing the risk of or delaying the occurrence of acardiovascular event in patients, for example patients with type 1 ortype 2 diabetes mellitus. The present invention also further relates tocertain SGLT-2 inhibitors for preventing, slowing, delaying or treatingthe degeneration of pancreatic beta cells and/or the decline of thefunctionality of pancreatic beta cells and/or for improving and/orrestoring the functionality of pancreatic beta cells and/or restoringthe functionality of pancreatic insulin secretion in patients havinglatent autoimmune diabetes in adults (LADA).

In one embodiment, the present invention provides a method for treatingand/or preventing oxidative stress, vascular stress and/or endothelialdysfunction comprising administering empagliflozin, optionally incombination with one or more other therapeutic substances, to a patientin need thereof. In one embodiment, the patient is a non-diabeticpatient or a patient with type 1 or type 2 diabetes mellitus. In oneembodiment, the method is for treating and/or preventing endothelialdysfunction in a patient with type 1 or type 2 diabetes mellitus.

In one embodiment, the present invention provides a method for treatingand/or preventing collagen deposition and/or vessel wall thickeningcomprising administering empagliflozin, optionally in combination withone or more other therapeutic substances, to a patient in need thereof.In one embodiment, the patient is a non-diabetic patient or a patientwith type 1 or type 2 diabetes mellitus. In one embodiment, the methodis for treating and/or preventing endothelial dysfunction in a patientwith type 1 or type 2 diabetes mellitus.

In one embodiment, the present invention provides a method of treatingtype 2 diabetes mellitus in a patient with or at risk of oxidativestress, vascular stress and/or endothelial dysfunction, or diseases orconditions related or associated therewith, said method comprisingadministering empagliflozin, optionally in combination with one or moreother therapeutic substances, to the patient.

In one embodiment, the present invention provides a method for usingempagliflozin in one or more of the following methods:

-   -   preventing, slowing the progression of, delaying or treating a        metabolic disorder selected from the group consisting of type 1        or type 2 diabetes mellitus, impaired glucose tolerance,        impaired fasting blood glucose, hyperglycemia, postprandial        hyperglycemia, hyperinsulinemia and metabolic syndrome; or    -   slowing the progression of, delaying or treating of        pre-diabetes; or    -   preventing, slowing the progression of, delaying or treating of        an onset of type 2 diabetes mellitus; or    -   improving glycemic control and/or for reducing of fasting plasma        glucose, of postprandial plasma glucose and/or of glycosylated        hemoglobin HbA1c; or    -   preventing, slowing, delaying or reversing progression from        impaired glucose tolerance, impaired fasting blood glucose,        insulin resistance or from metabolic syndrome to type 2 diabetes        mellitus; or    -   preventing, slowing the progression of, delaying or treating of        a condition or disorder selected from the group consisting of        complications of diabetes mellitus such as cataracts and micro-        and macrovascular diseases, such as nephropathy, retinopathy,        neuropathy, tissue ischaemia, diabetic foot, dyslipidemia,        arteriosclerosis, myocardial infarction, accute coronary        syndrome, unstable angina pectoris, stable angina pectoris,        stroke, peripheral arterial occlusive disease, cardiomyopathy,        heart failure, heart rhythm disorders and vascular restenosis;        or    -   reducing body weight and/or body fat, or preventing an increase        in body weight and/or body fat, or facilitating a reduction in        body weight and/or body fat; or    -   preventing, slowing, delaying or treating the degeneration of        pancreatic beta cells and/or the decline of the functionality of        pancreatic beta cells and/or for improving and/or restoring the        functionality of pancreatic beta cells and/or restoring the        functionality of pancreatic insulin secretion; or    -   preventing, slowing, delaying or treating diseases or conditions        attributed to an abnormal accumulation of ectopic fat, in        particular liver fat; or    -   for maintaining and/or improving the insulin sensitivity and/or        for treating or preventing hyperinsulinemia and/or insulin        resistance; in a patient with or at risk of oxidative stress,        vascular stress and/or endothelial dysfunction, or diseases or        conditions related or associated therewith, or        in a patient with or at risk of cardiovascular disease selected        from myocardial infarction, stroke, peripheral arterial        occlusive disease, or in a patient with one or more        cardiovascular risk factors selected from A), B), C) and D):        A) previous or existing vascular disease selected from        myocardial infarction, coronary artery disease, percutaneous        coronary intervention, coronary artery by-pass grafting,        ischemic or hemorrhagic stroke, congestive heart failure, and        peripheral occlusive arterial disease,        B) advanced age >/=60-70 years, and        C) one or more cardiovascular risk factors selected from    -   advanced type 1 or type 2 diabetes mellitus >10 years duration,    -   hypertension,    -   current daily cigarette smoking,    -   dyslipidemia,    -   obesity,    -   age >/=40    -   metabolic syndrome, hyperinsulinemia or insulin resistance, and    -   hyperuricemia, erectile dysfunction, polycystic ovary syndrome,        sleep apnea, or family history of vascular disease or        cardiomyopathy in first-degree relative;        D) one or more of the following:    -   confirmed history of myocardial infarction,    -   unstable angina with documented multivessel coronary disease or        positive stress test,    -   multivessel Percutaneous Coronary Intervention,    -   multivessel Coronary Artery By-pass Grafting (CABG),    -   history of ischemic or hemorrhagic stroke,    -   peripheral occlusive arterial disease.        said method comprising administering empagliflozin, optionally        in combination with one or more other therapeutic substances, to        the patient.

In one embodiment, the method comprises treating type 1 or type 2diabetes mellitus. In one embodiment, the patient is a type 1 or type 2diabetes mellitus patient with or at risk of a cardiovascular diseaseselected from myocardial infarction, stroke, peripheral arterialocclusive diasease.

In one embodiment, the patient is a patient with type 1 or type 2diabetes mellitus or with pre-diabetes with one or more cardiovascularrisk factors selected from A), B), C) and D):

A) previous or existing vascular disease selected from myocardialinfarction, coronary artery disease, percutaneous coronary intervention,coronary artery by-pass grafting, ischemic or hemorrhagic stroke,congestive heart failure, and peripheral occlusive arterial disease,B) advanced age >/=60-70 years, andC) one or more cardiovascular risk factors selected from

-   -   advanced type 1 or type 2 diabetes mellitus >10 years duration,    -   hypertension,    -   current daily cigarette smoking,    -   dyslipidemia,    -   obesity,    -   age >1=40,

metabolic syndrome, hyperinsulinemia or insulin resistance, and

-   -   hyperuricemia, erectile dysfunction, polycystic ovary syndrome,        sleep apnea, or family history of vascular disease or        cardiomyopathy in first-degree relative;        D) one or more of the following:    -   confirmed history of myocardial infarction,    -   unstable angina with documented multivessel coronary disease or        positive stress test,    -   multivessel Percutaneous Coronary Intervention,    -   multivessel Coronary Artery By-pass Grafting (CABG),    -   history of ischemic or hemorrhagic stroke,    -   peripheral occlusive arterial disease.

In another embodiment, the present invention provides a method ofpreventing, reducing the risk of or delaying the occurrence of acardiovascular event in a patient with type 1 or type 2 diabetesmellitus or with pre-diabetes, said method comprising administeringempagliflozin, optionally in combination with one or more othertherapeutic substances, to the patient. In one embodiment, thecardiovascular event is selected from cardiovascular death, non-fatalmyocardial infarction, non-fatal stroke, hospitalisation for unstableangina pectoris and heart failure requiring hospitalisation. In oneembodiment, the cardiovascular death is due to fatal myocardialinfarction or fatal stroke. In one embodiment, the patient has or is atrisk of a cardiovascular disease.

In one embodiment, the patient with type 1 or type 2 diabetes mellitusor with pre-diabetes has one or more cardiovascular risk factorsselected from A), B), C) and D):

A) previous or existing vascular disease selected from myocardialinfarction, coronary artery disease, percutaneous coronary intervention,coronary artery by-pass grafting, ischemic or hemorrhagic stroke,congestive heart failure, and peripheral occlusive arterial disease,B) advanced age >/=60-70 years, andC) one or more cardiovascular risk factors selected from

-   -   advanced type 1 or 2 diabetes mellitus >10 years duration,    -   hypertension,    -   current daily cigarette smoking,    -   dyslipidemia,    -   obesity,    -   age >/=40    -   metabolic syndrome, hyperinsulinemia or insulin resistance, and    -   hyperuricemia, erectile dysfunction, polycystic ovary syndrome,        sleep apnea, or family history of vascular disease or        cardiomyopathy in first-degree relative;        D) one or more of the following:    -   confirmed history of myocardial infarction,    -   unstable angina with documented multivessel coronary disease or        positive stress test,    -   multivessel Percutaneous Coronary Intervention,    -   multivessel Coronary Artery By-pass Grafting (CABG),    -   history of ischemic or hemorrhagic stroke,    -   peripheral occlusive arterial disease.

In one embodiment, the present invention provides a method of treating ametabolic disorder and preventing, reducing the risk of or delaying theoccurrence of a cardiovascular event in a patient comprisingadministering empagliflozin, optionally in combination with one or moreother therapeutic substances, to the patient. In one embodiment, themetabolic disorder is type 1 or 2 diabetes mellitus or pre-diabetes. Inone embodiment, the cardiovascular event is selected from cardiovasculardeath, non-fatal myocardial infarction, non-fatal stroke,hospitalisation for unstable angina pectoris and heart failure requiringhospitalisation.

In one embodiment, the patient with type type 1 or 2 diabetes mellitusor pre-diabetes has one or more cardiovascular risk factors selectedfrom A), B), C) and D):

A) previous or existing vascular disease selected from myocardialinfarction, coronary artery disease, percutaneous coronary intervention,coronary artery by-pass grafting, ischemic or hemorrhagic stroke,congestive heart failure, and peripheral occlusive arterial disease,B) advanced age >/=60-70 years, andC) one or more cardiovascular risk factors selected from

-   -   advanced type 2 diabetes mellitus >10 years duration,    -   hypertension,    -   current daily cigarette smoking,    -   dyslipidemia,    -   obesity,    -   age>/=40,    -   metabolic syndrome, hyperinsulinemia or insulin resistance, and    -   hyperuricemia, erectile dysfunction, polycystic ovary syndrome,        sleep apnea, or family history of vascular disease or        cardiomyopathy in first-degree relative;        D) one or more of the following:    -   confirmed history of myocardial infarction,    -   unstable angina with documented multivessel coronary disease or        positive stress test,    -   multivessel Percutaneous Coronary Intervention,    -   multivessel Coronary Artery By-pass Grafting (CABG),    -   history of ischemic or hemorrhagic stroke,    -   peripheral occlusive arterial disease.

In one embodiment, the present invention provides a method of treatmentcomprising:

-   -   a) identifying a patient in need of treatment for type 1 or type        2 diabetes and with or at risk of cardiovascular disease; and    -   b) administering empagliflozin to said patient.

In one embodiment, the present invention provides a method of treatmentcomprising:

-   -   a) selecting a patient with or at risk of cardiovascular disease        from a population of patients in need of treatment for type 1 or        type 2 diabetes mellitus;    -   b) selecting a type 1 or type 2 diabetes treatment that includes        empagliflozin; and    -   c) administering empagliflozin to the patient selected in step        a).

In one embodiment, the present invention provides a method ofpreventing, reducing the risk of or delaying the occurrence of acardiovascular event in a patient diagnosed with type 1 or type 2diabetes comprising:

-   -   a. determining the cardiovascular health of the patient;    -   b. identifying that the patient has or is at risk of a        cardiovascular disease;    -   c. administering empagliflozin to the patient.

In one aspect, empagliflozin is administered to the patient if thepatient has an elevated risk of a cardiovascular event.

In one embodiment, the patient has or is at risk of a cardiovasculardisease selected from myocardial infarction, stroke, peripheral arterialocclusive disease.

In one embodiment, the present invention provides a method for treatinga metabolic disorder in a patient comprising administering apharmaceutical composition comprising empagliflozin to said patient,wherein the risk or occurrence of a cardiovascular event in said patientis reduced. In one embodiment, the cardiovascular event is selected fromcardiovascular death, non-fatal myocardial infarction, non-fatal stroke,hospitalisation for unstable angina pectoris and heart failure requiringhospitalisation. In one embodiment, the risk or occurrence of acardiovascular event is reduced when compared to a patient administeredwith a placebo on standard of care background medication. In oneembodiment, the risk or occurrence of a cardiovascular event is reducedby 15% or more. In one embodiment, the risk or occurrence of acardiovascular event is reduced by 16% or more, by 17% or more, by 18%or more, by 19% or more, by 20% or more, by 25% or more or by 30% ormore. In one embodiment, pharmaceutical composition comprises 10 mg or25 mg of empagliflozin. In one embodiment, the metabolic disorder istype 1 or type 2 diabetes mellitus or pre-diabetes.

In one embodiment, the patient is a patient with type 1 or type 2diabetes or pre-diabetes with one or more cardiovascular risk factorsselected from A), B), C) and D):

A) previous or existing vascular disease selected from myocardialinfarction, coronary artery disease, percutaneous coronary intervention,coronary artery by-pass grafting, ischemic or hemorrhagic stroke,congestive heart failure, and peripheral occlusive arterial disease,B) advanced age >/=60-70 years, andC) one or more cardiovascular risk factors selected from

-   -   advanced type 1 or type 2 diabetes mellitus >10 years duration,    -   hypertension,    -   current daily cigarette smoking,    -   dyslipidemia,    -   obesity,    -   age >/=40,    -   metabolic syndrome, hyperinsulinemia or insulin resistance, and    -   hyperuricemia, erectile dysfunction, polycystic ovary syndrome,        sleep apnea, or family history of vascular disease or        cardiomyopathy in first-degree relative;        D) one or more of the following:    -   confirmed history of myocardial infarction,    -   unstable angina with documented multivessel coronary disease or        positive stress test,    -   multivessel Percutaneous Coronary Intervention,    -   multivessel Coronary Artery By-pass Grafting (CABG),    -   history of ischemic or hemorrhagic stroke,    -   peripheral occlusive arterial disease.

In one embodiment, the hazard ratio at a one-sided α-level of 0.025 is<1.3.

In one embodiment, the present invention provides a method for reducingarterial stiffness in a patient comprising administering empagliflozinto the patient. In one aspect, the patient is a patient according to thepresent invention, in particular a patient with type 1 or type 2diabetes or pre-diabetes.

In one aspect of the present invention, the one or more othertherapeutic substances are selected from other antidiabetic substances,active substances that lower the blood sugar level, active substancesthat lower the total cholesterol, LDL-cholesterol, Non-HDL-cholesteroland/or Lp(a) level in the blood, active substances that raise theHDL-cholesterol level in the blood, active substances that lower bloodpressure, active substances that are indicated in the treatment ofatherosclerosis or obesity, antiplatelet agents, anticoagulant agents,and vascular endothelial protective agents. In one embodiment, the otherantidiabetic substances are selected from metformin, sulphonylureas,nateglinide, repaglinide, PPAR-gamma agonists, alpha-glucosidaseinhibitors, insulin and insulin analogues, GLP-1 and GLP-1 analogues andDPP-4 inhibitors. In one embodiment, the active substances that lowerblood pressure are selected from angiotensin receptor blockers (ARB),angiotensin-converting enzyme (ACE) inhibitors, beta-blockers anddiuretics. In one aspect, the present invention comprises administeringempagliflozin in combination with one or more other antidiabeticsubstances selected from metformin, a sulphonylurea, nateglinide,repaglinide, a DPP-4 inhibitor, a PPAR-gamma agonist, analpha-glucosidase inhibitor, insulin or insulin analogue, and GLP-1 orGLP-1 analogue. In one aspect, the present invention comprisesadministering empagliflozin in combination with metformin. In oneaspect, the present invention comprises administering empagliflozin incombination with linagliptin. In one aspect, the present inventioncomprises administering empagliflozin in combination with metformin andlinagliptin. In one aspect, empagliflozin is administered orally in atotal daily amount of 10 mg or 25 mg.

In one embodiment, the present invention provides a method of treatmentcomprising:

-   -   a) identifying a patient with type 1 or type 2 diabetes treated        with a medication to treat a cardiovascular disease;    -   b) administering empagliflozin to said patient; and    -   c) reducing the dosage or regimen of said medication to treat a        cardiovascular disease in said patient, while continuing to        administer empagliflozin to said patient.

In one embodiment, the method further comprises monitoring the cardiachealth of said patient.

In one embodiment, the present invention provides a method of treatmentcomprising:

-   -   a. identifying a patient with type 1 or type 2 diabetes treated        with a plurality of medications to treat a cardiovascular        disease;    -   b. administering empagliflozin to said patient; and    -   c. reducing the number of medications to treat a cardiovascular        disease in said patient, while continuing to administer        empagliflozin to said patient.

In one embodiment, the method further comprises monitoring the cardiachealth of said patient.

In one embodiment, the present invention provides a method of treatmentcomprising:

-   -   a) determining the number, dosage and/or regimen of medications        to treat a cardiovascular disease in a patient diagnosed with        type 1 or type 2 diabetes;    -   b) selecting empagliflozin as a treatment for type 2 diabetes        for the patient; and    -   c) administering empagliflozin to the patient while reducing the        number and/or dosage of medications to treat a cardiovascular        disease.

In one embodiment, the present invention provides a method of treatmentcomprising:

-   -   a) administering empagliflozin to a patient diagnosed with type        type 1 or 2 diabetes;    -   b) monitoring the cardiac health of said patient;    -   c) adjusting the number, dosage and/or regimen of medications to        treat a cardiovascular disease in said patient, while continuing        to administer empagliflozin to the patient.

In one embodiment, the present invention provides a method of reducingthe risk of a fatal or nonfatal cardiovascular event in a type 1 or type2 diabetes patient comprising administering empagliflozin, optionally incombination with one or more other therapeutic substances, to thepatient.

In one embodiment, the fatal or nonfatal cardiovascular event is stroke,myocardial infarction or heart failure. In one embodiment, the patientis at elevated risk of a cardiovascular event.

In one embodiment the patient at elevated risk of a cardiovascular eventhas a history of coronary artery disease, peripheral arterial disease,stroke, transient ischemic attack or high-risk diabetes(insulin-dependent or non-insulin dependent) with evidence of end-organdamage. In one embodiment, the at least one of said one or more othertherapeutic substances is a medication to treat a cardiovasculardisease. In one embodiment, the one or more other therapeutic substancesis a medication that lower blood pressure are selected from angiotensinreceptor blockers (ARB), angiotensin-converting enzyme (ACE) inhibitors,and beta-blockers. In one embodiment, the one or more other therapeuticsubstances is a diuretic. In one embodiment, the number, dosage and/orregimen of said medications to treat a cardiovascular disease is reducedis said patient, while the administration of empagliflozin is continued.

In one embodiment, the present invention provides a method of reducingthe risk of myocardial infarction, stroke or death from cardiovascularcauses or heart failure, in particular heart failure requiringhospitalization, in a type 1 or type 2 diabetes patient comprisingadministering empagliflozin, optionally in combination with one or moreother therapeutic substances, to the patient. In one embodiment, thepatient is at elevated risk of a cardiovascular event. In oneembodiment, the patient at elevated risk of a cardiovascular event has ahistory of coronary artery disease, peripheral arterial disease, stroke,transient ischemic attack or high-risk diabetes (insulin-dependent ornon-insulin dependent) with evidence of end-organ damage. In oneembodiment, at least one of said one or more other therapeuticsubstances is a medication to treat a cardiovascular disease. In oneembodiment, the one or more other therapeutic substances is a medicationthat lower blood pressure are selected from angiotensin receptorblockers (ARB), angiotensin-converting enzyme (ACE) inhibitors, andbeta-blockers. In one embodiment, the one or more other therapeuticsubstances is a diuretic. In one embodiment, the number, dosage and/orregimen of said medications to treat a cardiovascular disease is reducedis said patient, while the administration of empagliflozin is continued.

In a further embodiment, the present invention provides a method forpreventing, slowing, delaying or treating the degeneration of pancreaticbeta cells and/or the decline of the functionality of pancreatic betacells and/or for improving and/or restoring the functionality ofpancreatic beta cells and/or restoring the functionality of pancreaticinsulin secretion in a patient having latent autoimmune diabetes inadults (LADA), the method comprising administering empagliflozin,optionally in combination with one or more other therapeutic substances,to the patient. In one embodiment, the patient having LADA is a patientin whom one or more autoantibodies selected from GAD (GAD-65, anti-GAD),ICA, IA-2A, ZnT8 (anti-ZnT 8) and IAA are present.

In a further embodiment, the present invention provides a method forpreserving pancreatic beta cells and/or their function in a patienthaving latent autoimmune diabetes in adults (LADA), the methodcomprising administering empagliflozin, optionally in combination withone or more other therapeutic substances, to the patient. In oneembodiment, the patient having LADA is a patient in whom one or moreautoantibodies selected from GAD (GAD-65, anti-GAD), ICA, IA-2A, ZnT8(anti-ZnT8) and IAA are present.

In a further embodiment, the present invention provides a method forstimulating and/or protecting the functionality of pancreatic insulinsecretion in a patient having latent autoimmune diabetes in adults(LADA), the method comprising administering empagliflozin, optionally incombination with one or more other therapeutic substances, to thepatient. In one embodiment, the patient having LADA is a patient in whomone or more autoantibodies selected from GAD (GAD-65, anti-GAD), ICA,IA-2A, ZnT8 (anti-ZnT8) and IAA are present.

In a further embodiment, the present invention provides a method fortreating and/or preventing LADA (latent autoimmune diabetes of adults),particularly in a patient having LADA in whom one or more autoantibodiesselected from GAD (GAD-65, anti-GAD), ICA, IA-2A, ZnT8 (anti-ZnT8) andIAA are present, the method comprising administering empagliflozin,optionally in combination with one or more other therapeutic substances,to the patient.

In one aspect of the present invention, empagliflozin is administeredorally, for example in a total daily amount of 10 mg or 25 mg. In oneembodiment, empagliflozin is administered as a pharmaceuticalcomposition comprising 10 mg or 25 mg of empagliflozin, for example as atablet.

In one aspect of the present invention, in a method or use disclosedherein a patient is patient with type 2 diabetes (or type 2 diabetespatient), a patient treated for type 2 diabetes, a patient diagnosedwith type 2 diabetes or a patient in need of treatment for type 2diabetes. In one aspect, a patient is a patient with pre-diabetes.

The present invention further provides for empagliflozin or apharmaceutical composition comprising empagliflozin for use as amedicament in any one of the methods described herein.

The present invention further provides for empagliflozin or apharmaceutical composition comprising empagliflozin for use in thetreatment of any one of the diseases or conditions described herein.

The present invention further provides for empagliflozin or apharmaceutical composition comprising empagliflozin for use in themanufacture of a medicament for use in any one of the methods describedherein.

DEFINITIONS

The term “active ingredient” of a pharmaceutical composition accordingto the present invention means the SGLT2 inhibitor according to thepresent invention. An “active ingredient is also sometimes referred toherein as an “active substance”.

The term “body mass index” or “BMI” of a human patient is defined as theweight in kilograms divided by the square of the height in meters, suchthat BMI has units of kg/m².

The term “overweight” is defined as the condition wherein the individualhas a BMI greater than or 25 kg/m² and less than 30 kg/m². The terms“overweight” and “pre-obese” are used interchangeably.

The terms “obesity” or “being obese” and the like are defined as thecondition wherein the individual has a BMI equal to or greater than 30kg/m². According to a WHO definition the term obesity may be categorizedas follows: the term “class I obesity” is the condition wherein the BMIis equal to or greater than 30 kg/m² but lower than 35 kg/m²; the term“class II obesity” is the condition wherein the BMI is equal to orgreater than 35 kg/m² but lower than 40 kg/m²; the term “class IIIobesity” is the condition wherein the BMI is equal to or greater than 40kg/m².

The indication obesity includes in particular exogenic obesity,hyperinsulinaemic obesity, hyperplasmic obesity, hyperphyseal adiposity,hypoplasmic obesity, hypothyroid obesity, hypothalamic obesity,symptomatic obesity, infantile obesity, upper body obesity, alimentaryobesity, hypogonadal obesity, central obesity, visceral obesity,abdominal obesity.

The term “visceral obesity” is defined as the condition wherein awaist-to-hip ratio of greater than or equal to 1.0 in men and 0.8 inwomen is measured. It defines the risk for insulin resistance and thedevelopment of pre-diabetes.

The term “abdominal obesity” is usually defined as the condition whereinthe waist circumference is >40 inches or 102 cm in men, and is >35inches or 94 cm in women. With regard to a Japanese ethnicity orJapanese patients abdominal obesity may be defined as waistcircumference 85 cm in men and 90 cm in women (see e.g. investigatingcommittee for the diagnosis of metabolic syndrome in Japan).

The term “euglycemia” is defined as the condition in which a subject hasa fasting blood glucose concentration within the normal range, greaterthan 70 mg/dL (3.89 mmol/L) and less than 100 mg/dL (5.6 mmol/L). Theword “fasting” has the usual meaning as a medical term.

The term “hyperglycemia” is defined as the condition in which a subjecthas a fasting blood glucose concentration above the normal range,greater than 100 mg/dL (5.6 mmol/L). The word “fasting” has the usualmeaning as a medical term.

The term “hypoglycemia” is defined as the condition in which a subjecthas a blood glucose concentration below the normal range, in particularbelow 70 mg/dL (3.89 mmol/L).

The term “postprandial hyperglycemia” is defined as the condition inwhich a subject has a 2 hour postprandial blood glucose or serum glucoseconcentration greater than 200 mg/dL (11.11 mmol/L).

The term “impaired fasting blood glucose” or “IFG” is defined as thecondition in which a subject has a fasting blood glucose concentrationor fasting serum glucose concentration in a range from 100 to 125 mg/dl(i.e. from 5.6 to 6.9 mmol/l), in particular greater than 110 mg/dL andless than 126 mg/dl (7.00 mmol/L). A subject with “normal fastingglucose” has a fasting glucose concentration smaller than 100 mg/dl,i.e. smaller than 5.6 mmol/l.

The term “impaired glucose tolerance” or “IGT” is defined as thecondition in which a subject has a 2 hour postprandial blood glucose orserum glucose concentration greater than 140 mg/dl (7.78 mmol/L) andless than 200 mg/dL (11.11 mmol/L). The abnormal glucose tolerance, i.e.the 2 hour postprandial blood glucose or serum glucose concentration canbe measured as the blood sugar level in mg of glucose per dL of plasma 2hours after taking 75 g of glucose after a fast. A subject with “normalglucose tolerance” has a 2 hour postprandial blood glucose or serumglucose concentration smaller than 140 mg/dl (7.78 mmol/L).

The term “hyperinsulinemia” is defined as the condition in which asubject with insulin resistance, with or without euglycemia, has fastingor postprandial serum or plasma insulin concentration elevated abovethat of normal, lean individuals without insulin resistance, having awaist-to-hip ratio<1.0 (for men) or <0.8 (for women).

The terms “insulin-sensitizing”, “insulin resistance-improving” or“insulin resistance-lowering” are synonymous and used interchangeably.

The term “insulin resistance” is defined as a state in which circulatinginsulin levels in excess of the normal response to a glucose load arerequired to maintain the euglycemic state (Ford E S, et al. JAMA. (2002)287:356-9). A method of determining insulin resistance is theeuglycaemic-hyperinsulinaemic clamp test. The ratio of insulin toglucose is determined within the scope of a combined insulin-glucoseinfusion technique. There is found to be insulin resistance if theglucose absorption is below the 25th percentile of the backgroundpopulation investigated (WHO definition). Rather less laborious than theclamp test are so called minimal models in which, during an intravenousglucose tolerance test, the insulin and glucose concentrations in theblood are measured at fixed time intervals and from these the insulinresistance is calculated. With this method, it is not possible todistinguish between hepatic and peripheral insulin resistance.

Furthermore, insulin resistance, the response of a patient with insulinresistance to therapy, insulin sensitivity and hyperinsulinemia may bequantified by assessing the “homeostasis model assessment to insulinresistance (HOMA-IR)” score, a reliable indicator of insulin resistance(Katsuki A, et al. Diabetes Care 2001; 24: 362-5). Further reference ismade to methods for the determination of the HOMA-index for insulinsensitivity (Matthews et al., Diabetologia 1985, 28:412-19), of theratio of intact proinsulin to insulin (Forst et al., Diabetes 2003,52(Suppl.1): A459) and to an euglycemic clamp study. In addition, plasmaadiponectin levels can be monitored as a potential surrogate of insulinsensitivity. The estimate of insulin resistance by the homeostasisassessment model (HOMA)-IR score is calculated with the formula (GalvinP, et al. Diabet Med 1992; 9:921-8):

HOMA-IR=[fasting serum insulin (μU/mL)]×[fasting plasmaglucose(mmol/L)/22.5]

Insulin resistance can be confirmed in these individuals by calculatingthe HOMA-IR score. For the purpose of this invention, insulin resistanceis defined as the clinical condition in which an individual has aHOMA-IR score >4.0 or a HOMA-IR score above the upper limit of normal asdefined for the laboratory performing the glucose and insulin assays.

As a rule, other parameters are used in everyday clinical practice toassess insulin resistance. Preferably, the patient's triglycerideconcentration is used, for example, as increased triglyceride levelscorrelate significantly with the presence of insulin resistance.

Individuals likely to have insulin resistance are those who have two ormore of the following attributes: 1) overweight or obese, 2) high bloodpressure, 3) hyperlipidemia, 4) one or more 1^(st) degree relative witha diagnosis of IGT or IFG or type 2 diabetes.

Patients with a predisposition for the development of IGT or IFG or type2 diabetes are those having euglycemia with hyperinsulinemia and are bydefinition, insulin resistant. A typical patient with insulin resistanceis usually overweight or obese. If insulin resistance can be detected,this is a particularly strong indication of the presence ofpre-diabetes. Thus, it may be that in order to maintain glucosehomoeostasis a person needs 2-3 times as much insulin as a healthyperson, without this resulting in any clinical symptoms.

“Pre-diabetes” is a general term that refers to an intermediate stagebetween normal glucose tolerance (NGT) and overt type 2 diabetesmellitus (T2DM), also referred to as intermediate hyperglycaemia. Assuch, it represents 3 groups of individuals, those with impaired glucosetolerance (IGT) alone, those with impaired fasting glucose (IFG) aloneor those with both IGT and IFG. IGT and IFG usually have distinctpathophysiologic etiologies, however also a mixed condition withfeatures of both can exist in patients. Therefore in the context of thepresent invention a patient being diagnosed of having “pre-diabetes” isan individual with diagnosed IGT or diagnosed IFG or diagnosed with bothIGT and IFG.

Following the definition according to the American Diabetes Association(ADA) and in the context of the present invention a patient beingdiagnosed of having “pre-diabetes” is an individual with:

a) a fasting plasma glucose (FPG) concentration <100 mg/dL [1mg/dL=0.05555 mmol/L] and a 2-hour plasma glucose (PG) concentration,measured by a 75-g oral glucose tolerance test (OGTT), ranging between140 mg/dL and <200 mg/dL (i.e., IGT); orb) a fasting plasma glucose (FPG) concentration between 00 mg/dL and<126 mg/dL and a 2-hour plasma glucose (PG) concentration, measured by a75-g oral glucose tolerance test (OGTT) of <140 mg/dL (i.e., IFG); orc) a fasting plasma glucose (FPG) concentration between 00 mg/dL and<126 mg/dL and a 2-hour plasma glucose (PG) concentration, measured by a75-g oral glucose tolerance test (OGTT), ranging between 140 mg/dL and<200 mg/dL (i.e., both IGT and IFG).

Patients with “pre-diabetes” are individuals being pre-disposed to thedevelopment of type 2 diabetes. Pre-diabetes extends the definition ofIGT to include individuals with a fasting blood glucose within the highnormal range ≧100 mg/dL (J. B. Meigs, et al. Diabetes 2003;52:1475-1484). The scientific and medical basis for identifyingpre-diabetes as a serious health threat is laid out in a PositionStatement entitled “The Prevention or Delay of Type 2 Diabetes” issuedjointly by the American Diabetes Association and the National Instituteof Diabetes and Digestive and Kidney Diseases (Diabetes Care 2002;25:742-749).

The methods to investigate the function of pancreatic beta-cells aresimilar to the above methods with regard to insulin sensitivity,hyperinsulinemia or insulin resistance: An improvement of beta-cellfunction can be measured for example by determining a HOMA-index(homeostasis model assessment) for beta-cell function, HOMA-B, (Matthewset al., Diabetologia 1985, 28:412-19), the ratio of intact proinsulin toinsulin (Forst et al., Diabetes 2003, 52(Suppl.1): A459), first andsecond phase insulin secretion after an oral glucose tolerance test or ameal tolerance test (Stumvoll et al., Diabetes care 2000, 23: 295-301),the insulin/C-peptide secretion after an oral glucose tolerance test ora meal tolerance test, or by employing a hyperglycemic clamp studyand/or minimal modeling after a frequently sampled intravenous glucosetolerance test (Stumvoll et al., Eur J Clin Invest 2001, 31: 380-81).

The term “type 1 diabetes” is defined as the condition in which asubject has, in the presence of autoimmunity towards the pancreaticbeta-cell or insulin, a fasting blood glucose or serum glucoseconcentration greater than 125 mg/dL (6.94 mmol/L). If a glucosetolerance test is carried out, the blood sugar level of a diabetic willbe in excess of 200 mg of glucose per dL (11.1 mmol/l) of plasma 2 hoursafter 75 g of glucose have been taken on an empty stomach, in thepresence of autoimmunity towards the pancreatic beta cell or insulin. Ina glucose tolerance test 75 g of glucose are administered orally to thepatient being tested after 10-12 hours of fasting and the blood sugarlevel is recorded immediately before taking the glucose and 1 and 2hours after taking it. The presence of autoimmunity towards thepancreatic beta-cell may be observed by detection of circulating isletcell autoantibodies [“type 1A diabetes mellitus”], i.e., at least oneof: GAD65 [glutamic acid decarboxylase-65], ICA [islet-cell cytoplasm],IA-2 [intracytoplasmatic domain of the tyrosine phosphatase-like proteinIA-2], ZnT8 [zinc-transporter-8] or anti-insulin; or other signs ofautoimmunity without the presence of typical circulating autoantibodies[type 1B diabetes], i.e. as detected through pancreatic biopsy orimaging). Typically a genetic predisposition is present (e.g. HLA, INSVNTR and PTPN22), but this is not always the case.

The term “type 2 diabetes mellitus” or “T2DM” is defined as thecondition in which a subject has a fasting blood glucose or serumglucose concentration greater than 125 mg/dL (6.94 mmol/L). Themeasurement of blood glucose values is a standard procedure in routinemedical analysis. If a glucose tolerance test is carried out, the bloodsugar level of a diabetic will be in excess of 200 mg of glucose per dL(11.1 mmol/l) of plasma 2 hours after 75 g of glucose have been taken onan empty stomach. In a glucose tolerance test 75 g of glucose areadministered orally to the patient being tested after 10-12 hours offasting and the blood sugar level is recorded immediately before takingthe glucose and 1 and 2 hours after taking it. In a healthy subject, theblood sugar level before taking the glucose will be between 60 and 110mg per dL of plasma, less than 200 mg per dL 1 hour after taking theglucose and less than 140 mg per dL after 2 hours. If after 2 hours thevalue is between 140 and 200 mg, this is regarded as abnormal glucosetolerance.

The term “late stage type 2 diabetes mellitus” includes patients with asecondary drug failure, indication for insulin therapy and progressionto micro- and macrovascular complications e.g. diabetic nephropathy, orcoronary heart disease (CHD).

The term “LADA” (“latent autoimmune diabetes of adults”) refers topatients that have a clinical diagnosis of type 2 diabetes, but who arebeing detected to have autoimmunity towards the pancreatic beta cell.Latent autoimmune diabetes of adults (LADA) is also known as slowlyprogressive type 1 diabetes mellitus (T1 DM), “mild” T1 DM, non-insulindependent type 1 DM, type 1½ DM, double diabetes or antibody positivetype 2 DM (T2DM). LADA is often not clearly defined and, opposed to T1DM, seldom or never presents with significant weight loss andketoacidosis due to rapidly progressive β-cell failure.

The term “HbA1c” refers to the product of a non-enzymatic glycation ofthe haemoglobin B chain. Its determination is well known to one skilledin the art. In monitoring the treatment of diabetes mellitus the HbA1cvalue is of exceptional importance. As its production dependsessentially on the blood sugar level and the life of the erythrocytes,the HbA1c in the sense of a “blood sugar memory” reflects the averageblood sugar levels of the preceding 4-6 weeks. Diabetic patients whoseHbA1c value is consistently well adjusted by intensive diabetestreatment (i.e. <6.5% of the total haemoglobin in the sample), aresignificantly better protected against diabetic microangiopathy. Forexample, metformin on its own achieves an average improvement in theHbA1c value in the diabetic of the order of 1.0-1.5%. This reduction ofthe HbA1C value is not sufficient in all diabetics to achieve thedesired target range of <7% or <6.5% and preferably <6% HbA1c.

The term “insufficient glycemic control” or “inadequate glycemiccontrol” in the scope of the present invention means a condition whereinpatients show HbA1c values above 6.5%, in particular above 7.0%, evenmore preferably above 7.5%, especially above 8%.

The “metabolic syndrome”, also called “syndrome X” (when used in thecontext of a metabolic disorder), also called the “dysmetabolicsyndrome” is a syndrome complex with the cardinal feature being insulinresistance (Laaksonen D E, et al. Am J Epidemiol 2002; 156:1070-7).According to the ATP III/NCEP guidelines (Executive Summary of the ThirdReport of the National Cholesterol Education Program (NCEP) Expert Panelon Detection, Evaluation, and Treatment of High Blood Cholesterol inAdults (Adult Treatment Panel III) JAMA: Journal of the American MedicalAssociation (2001) 285:2486-2497), diagnosis of the metabolic syndromeis made when three or more of the following risk factors are present:

-   -   1. Abdominal obesity, defined as waist circumference >40 inches        or 102 cm in men, and >35 inches or 94 cm in women; or with        regard to a Japanese ethnicity or Japanese patients defined as        waist circumference 85 cm in men and 90 cm in women;    -   2. Triglycerides: 150 mg/dL    -   3. HDL-cholesterol <40 mg/dL in men    -   4. Blood pressure 130/85 mm Hg (SBP 130 or DBP 85)    -   5. Fasting blood glucose 100 mg/dL

The NCEP definitions have been validated (Laaksonen D E, et al. Am J.Epidemiol. (2002) 156:1070-7). Triglycerides and HDL cholesterol in theblood can also be determined by standard methods in medical analysis andare described for example in Thomas L (Editor): “Labor and Diagnose”,TH-Books Verlagsgesellschaft mbH, Frankfurt/Main, 2000.

According to a commonly used definition, hypertension is diagnosed ifthe systolic blood pressure (SBP) exceeds a value of 140 mm Hg anddiastolic blood pressure (DBP) exceeds a value of 90 mm Hg. If a patientis suffering from manifest diabetes it is currently recommended that thesystolic blood pressure be reduced to a level below 130 mm Hg and thediastolic blood pressure be lowered to below 80 mm Hg.

The term “empagliflozin” refers to the SGLT2 inhibitor1-chloro-4-(β-D-glucopyranos-1-yl)-2-[4-((S)-tetrahydrofuran-3-yloxy)-benzyl]-benzeneof the formula

as described for example in WO 2005/092877. Methods of synthesis aredescribed in the literature, for example WO 06/120208 and WO2011/039108. According to this invention, it is to be understood thatthe definition of empagliflozin also comprises its hydrates, solvatesand polymorphic forms thereof, and prodrugs thereof. An advantageouscrystalline form of empagliflozin is described in WO 2006/117359 and WO2011/039107 which hereby are incorporated herein in their entirety. Thiscrystalline form possesses good solubility properties which enables agood bioavailability of the SGLT2 inhibitor. Furthermore, thecrystalline form is physico-chemically stable and thus provides a goodshelf-life stability of the pharmaceutical composition. Preferredpharmaceutical compositions, such as solid formulations for oraladministration, for example tablets, are described in WO 2010/092126,which hereby is incorporated herein in its entirety.

The terms “treatment” and “treating” comprise therapeutic treatment ofpatients having already developed said condition, in particular inmanifest form. Therapeutic treatment may be symptomatic treatment inorder to relieve the symptoms of the specific indication or causaltreatment in order to reverse or partially reverse the conditions of theindication or to stop or slow down progression of the disease. Thus thecompositions and methods of the present invention may be used forinstance as therapeutic treatment over a period of time as well as forchronic therapy.

The terms “prophylactically treating”, “preventivally treating” and“preventing” are used interchangeably and comprise a treatment ofpatients at risk to develop a condition mentioned hereinbefore, thusreducing said risk.

The term “tablet” comprises tablets without a coating and tablets withone or more coatings. Furthermore the “term” tablet comprises tabletshaving one, two, three or even more layers and press-coated tablets,wherein each of the beforementioned types of tablets may be without orwith one or more coatings. The term “tablet” also comprises mini, melt,chewable, effervescent and orally disintegrating tablets.

The terms “pharmacopoe” and “pharmacopoeias” refer to standardpharmacopoeias such as the “USP 31-NF 26 through Second Supplement”(United States Pharmacopeial Convention) or the “European Pharmacopoeia6.3” (European Directorate for the Quality of Medicines and Health Care,2000-2009).

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1A-C: weight gain, blood glucose (non-fasting and fasting, n=6-8)and HbA1c (n=5-6) in animals treated with empagliflozin.

FIGS. 2A and 2B: relaxation (endothelial function) deteriorated in STZtreated (diabetic) animal and after treatment with empagliflozin. TheGTN curve on FIG. 2B is the positive control to show that in Nitricoxide supplies, all tissues equivalent showing the integrity of thevessels wall.

FIG. 3: oxidative burst (leukocyte-derived reactive oxygen species(ROS)) in blood upon ZymA stimulation at 30 minutes.

FIG. 4: oxidative burst (leukocyte-derived ROS) in blood upon ZymAstimulation at 60 minutes.

FIG. 5: time course of oxidative burst (leukocyte-derived ROS) in bloodupon ZymA stimulation.

FIG. 6: oxidative burst (leukocyte-derived ROS) in blood upon ZymAstimulation (at 30 minutes) with inhibitors of Nox2 activity (VAS2870)and an intracellular calcium chelator.

FIG. 7: oxidative burst (leukocyte-derived ROS) in blood upon ZymAstimulation (at 60 minutes) with inhibitors of Nox2 activity (VAS2870)and an intracellular calcium chelator.

FIG. 8: oxidative burst (leukocyte-derived ROS) in blood upon PDBustimulation at 15 minutes.

FIG. 9: time course of oxidative burst (leukocyte-derived ROS) in bloodupon PDBu stimulation.

FIG. 10: membraneous NADPH oxidase activity.

FIGS. 11A and 11B: liver ALDH-2 activity.

FIGS. 12A and 12B: vascular superoxide formation by fluorescent DHEmicrotopography.

FIG. 13 A-D: serum levels of cholesterol, triglyceride, insulin andinterferon-gamma, respectively.

FIG. 14: Hourly mean Systolic Blood Pressure (SBP) at Week 12 (mmHg).

FIG. 15: Hourly mean Systolic Blood Pressure (SBP) at Week 12 (mmHg).

FIGS. 16A and 16B: microscopic determination of aortic wall thicknessand collagen content by sirius red staining of aortic paraffinatedsections.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to certain SGLT-2 inhibitors, inparticular empagliflozin, for treating and/or preventing oxidativestress, for example in patients with type 1 or type 2 diabetes. Thepresent invention further relates to certain SGLT-2 inhibitors, inparticular empagliflozin, for treating and/or preventing endothelialdysfunction. The present invention further relates to certain SGLT-2inhibitors, in particular empagliflozin, to reduce glucotoxicity andassociated oxidative stress and inflammation in the tissues. The presentinvention also relates to the use of such SGLT-2 inhibitors in thetreatment and/or prevention of cardiovascular diseases in patients, forexample in type 1 or type 2 diabetes patients. The present inventionalso relates to the use of such SGLT-2 inhibitors, in particularempagliflozin, in treatment and/or prevention of metabolic disorders inpatients with or at risk of cardiovascular disease. The presentinvention further relates to certain SGLT-2 inhibitors, in particularempagliflozin, for treating and/or preventing a metabolic disorder andpreventing, reducing the risk of or delaying the occurrence of acardiovascular event in patients, for example patients with type 1 ortype 2 diabetes.

The present invention further relates to certain SGLT-2 inhibitors, inparticular empagliflozin, for treating and/or preventing oxidativestress, vascular stress and/or endothelial dysfunction (e.g. in diabetesor non-diabetes patients), particularly independently from or beyondglycemic control.

The present invention further relates to certain SGLT-2 inhibitors, inparticular empagliflozin, for treating and/or preventing collagendeposition and/or vessel wall thickening (e.g. in diabetes ornon-diabetes patients), particularly independently from or beyondglycemic control.

The present invention further relates to certain SGLT-2 inhibitors, inparticular empagliflozin, for treating and/or preventinghyperglycemia-induced or -associated oxidative stress (e.g. beyondglycemic control), as well as to the use of such SGLT-2 inhibitors inantidiabetic therapy.

The present invention further relates to certain SGLT-2 inhibitors, inparticular empagliflozin, for treating and/or preventing metabolicdisorders, such as diabetes, especially type 1 and type 2 diabetesmellitus and/or diseases related thereto (e.g. diabetic complications),particularly in patients having or being at risk of oxidative stress,vascular stress and/or endothelial dysfunction, or diseases orconditions related or associated therewith.

Further, the present invention relates to certain SGLT-2 inhibitors, inparticular empagliflozin, for treating and/or preventing metabolicdisorders, such as diabetes, especially type 1 and type 2 diabetesmellitus and/or diseases related thereto (e.g. diabetic complications),in patients having or being at risk of cardiovascular disease, such ase.g. myocardial infarction, stroke or peripheral arterial occlusivedisease, or micro- or macroalbuminuria.

Further, the present invention relates to certain SGLT-2 inhibitors, inparticular empagliflozin, for treating and/or preventing metabolicdisorders, such as diabetes, especially type 1 and type 2 diabetesmellitus and/or diseases related thereto, in patients having or being atrisk of micro- or macrovascular diabetic complications, such as e.g.diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, orcardiovascular diseases (such as e.g. myocardial infarction, stroke orperipheral arterial occlusive diasease).

Further, the present invention relates to certain SGLT-2 inhibitors, inparticular empagliflozin, for modulating, blocking or reducingdeleterious metabolic memory effect of (chronic or transient episodesof) hyperglycemia, particularly on diabetic complications.

Further, the present invention relates to certain SGLT-2 inhibitors, inparticular empagliflozin, for treating, preventing or reducing risk formicro- or macrovascular diseases which may be induced, memorized by orassociated with exposure to oxidative stress.

Furthermore, the present invention relates to a certain SGLT-2inhibitor, in particular empagliflozin, for treating and/or preventingmetabolic disorders, such as diabetes, especially type 1 and type 2diabetes mellitus and/or diseases related thereto (e.g. diabeticcomplications), in patients with or at risk of cardiovascular disease,particularly in those type 1 or type 2 diabetes patients being at riskof cardiovascular events, such as type 1 or type 2 diabetes patientswith one or more risk factors selected from previous or existingvascular disease (such as e.g. myocardial infarction (e.g. silent ornon-silent), coronary artery disease, percutaneous coronaryintervention, coronary artery by-pass grafting, ischemic or hemorrhagicstroke, congestive heart failure (e.g. NYHA class I or II, e.g. leftventricular function <40%), or peripheral occlusive arterial disease),said method comprising administering a therapeutically effective amountof the SGLT-2 inhibitor, optionally in combination with one or moreother therapeutic substances, to the patient.

Oxidative stress represents an imbalance between the production ofreactive oxygen species (which include free radicals, which typicallyhave an oxygen- or nitrogen based unpaired electron in their outerorbitals and peroxides) and a biological system's ability to readilydetoxify the reactive intermediates or to repair the resulting damage.Disturbances in the normal redox state of tissues can cause toxiceffects through the production of peroxides and free radicals thatdamage all components of the cell, including proteins, lipides andnucleic acid/DNA. Oxidative stress can target many organs (such as bloodvessels, eyes, heart, skin, kidney, joints, lung, brain, immune system,liver, or multi-organs) and can be involved in many diseases andconditions. Examples of such diseases or conditions associated withoxidative stress include atherosclerosis (e.g. platelet activation andatheromatous plaque formation), endothelial dysfunction, restenosis,hypertension, peripheral occlusive vascular disease,ischemia-reperfusion injuries (e.g. renal, hepatic, cardiac or cerebralischemia-reperfusion injuries), fibrosis (e.g. renal, hepatic, cardiacor pulmonary fibrosis); macular degeneration, retinal degeneration,cateracts, retinopathy; coronary heart disease, ischemia, myocardialinfarction; psoriasis, dermatitis; chronic kidney disease, nephritis,acute renal failure, glomerulonephritis, nephropathy; rheumatoidarthritis, osteoarthritis; asthma, COPD, respiratory distress syndrome;stroke, neurodegenerative diseases (e.g. Alzheimer's disease,Parkinson's disease, Huntington's disease), schizophrenia, bipolardisorder, obsessive compulsive disorder; chronic systemic inflammations,perivascular inflammation, autoimmune disorders, multiple sclerosis,lupus erythematosus, inflammatory bowel disease, ulcerative colitis;NAFLD/NASH; chronic fatigue syndrome, polycystic ovary syndrome, sepsis,diabetes, metabolic syndrome, insulin resistance, hyperglycemia,hyperinsulinemia, dyslipidemia, hypercholesterolemia, hyperlipidemia,etc. In addition to their original pharmacological properties, certaindrugs used clinically, including, without being limited,anti-hypertension agents, angiotensin receptor blockers andantihyperlipidemic agents such as statins, protect various organs viaanti-oxidative stress mechanisms.

Patients with or at risk of oxidative and/or vascular stress can bediagnosed by determining patient's oxidative stress markers, such ase.g. oxidized LDL, markers of inflammatory status (e.g. pro-inflammatoryinterleukins), 8-OHdG, isoprostanes (e.g. F2-isoprostanes,8-iso-prostaflandin F2alpha), nitrotyrosine, or N-carboxymethyl lysine(CML).

Endothelial dysfunction, commonly assessed clinically as impairedendothelium-dependent vasomotion (e.g. imbalance between vasodilatingand vasoconstricting), is a physiological disability of endothelialcells, the cells that line the inner surface of blood vessels, arteriesand veins, that prevents them from carrying out their normal biochemicalfunctions. Normal endothelial cells are involved in mediating theprocesses of coagulation, platelet adhesion, immune function, control ofvolume and electrolyte content of the intravascular and extravascularspaces. Endothelial dysfunction is associated with proinflammatory,pro-oxidative and prothrombotic changes within the arterial wall as wellas increase vessel wall thickness and collagen content. Endothelialdysfunction is thought to be a key event in the development andprogression of atherosclerosis and arterial stiffness, and predatesclinically obvious vascular complications. Endothelial dysfunction is ofprognostic significance in detecting vascular disease and predictingadverse vascular events. Risk factors for atherosclerosis and vasculardisease/events are associated with endothelial dysfunction. Endothelialdamage also contributes to the development of renal injury and/orchronic or progressive kidney damages, such as e.g. tubulointerstitialfibrosis, glomerulonephritis, micro-or macroalbuminuria, nephropathyand/or chronic kidney disease or renal failure. There is supportingevidence that oxidative stress does not only contribute to endothelialdysfunction or damage but also to vascular disease.

Type 2 diabetes mellitus is a common chronic and progressive diseasearising from a complex pathophysiology involving the dual endocrineeffects of insulin resistance and impaired insulin secretion with theconsequence not meeting the required demands to maintain plasma glucoselevels in the normal range. This leads to hyperglycaemia and itsassociated micro- and macrovascular complications or chronic damages,such as e.g. diabetic nephropathy, retinopathy or neuropathy, ormacrovascular (e.g. cardiovascular) complications. The vascular diseasecomponent plays a significant role, but is not the only factor in thespectrum of diabetes associated disorders. The high frequency ofcomplications leads to a significant reduction of life expectancy.Diabetes is currently the most frequent cause of adult-onset loss ofvision, renal failure, and amputation in the Industrialised Worldbecause of diabetes induced complications and is associated with a twoto five fold increase in cardiovascular disease risk. Type 1 diabetesmellitus (Type 1 diabetes), also called insulin dependent diabetesmellitus or juvenile diabetes, is a form of diabetes mellitus thatresults from autoimmune destruction of insulin-producing beta cells ofthe pancreas. The subsequent lack of insulin leads to increased bloodglucose concentrations and increased urinary glucose excretion. Theclassical symptoms are polyuria, polydipsia, polyphagia, and weightloss. Type 1 diabetes may be fatal unless treated with insulin.Complications from type 1 diabetes are the same or similar tocomplications from type 2 diabetes.

Large randomized studies have established that intensive and tightglycemic control during early (newly diagnoses to 5 years) stagediabetes has enduring beneficial effects and reduces the risk ofdiabetic complications, both micro- and macrovascular. However, manypatients with diabetes still develop diabetic complications despitereceiving intensified glycemic control.

Epidemiological and prospective data support a long-term influence ofearly (newly diagnosed to 5 years) metabolic control on clinicaloutcomes. It has been found that hyperglycemia has long-lastingdeleterious effects both in type 1 and type 2 diabetes and that glycemiccontrol, if not started at a very early stage of the disease or notintensively or not tightly provided, may not be enough to completelyreduce complications.

It has been further found that transient episodes of hyperglycemia (e.g.hyperglycemic events), can induce molecular changes, and that thesechanges can persist or are irreversible after return to normoglycemia.

Collectively, these data suggest that metabolic memories are storedearly in the course of diabetes and that, in certain diabeticconditions, oxidative and/or vascular stresses can persist after glucosenormalization. This phenomenon that early glycemic environment, and/oreven transient hyperglycemia, is remembered with clinical consequencesin the target end organs (e.g. blood vessels, retina, kidney, heart,extremities) has recently been termed as ‘metabolic memory.’

Potential mechanisms for propagating this ‘memory’ are certainepigenetic changes, the non-enzymatic glycation of cellular proteins andlipids (e.g. formation of advanced glycation end-products), oxidativelymodified atherogenic lipoproteins, and/or an excess of cellular reactiveoxygen and nitrogen species (RONS), in particular originated at thelevel of glycated-mitochondrial proteins, perhaps acting in concert withone another to maintain stress signalling.

Mitochondria are one of major sources of recative oxygen species (ROS)in cells.

Mitochondrial dysfunction increases electron leak and the generation ofROS from the mitochondrial respiratory chain (MRC). High levels ofglucose and lipids impair the activities of MRC complex enzymes. Forexample, the MRC enzyme NADPH oxidase generates superoxide from NADPH incells. Increased NADPH oxidase activity can be detected in diabeticpatients.

Further, there is evidence that overproduction of free radicals, such ase.g. reactive oxygen species (ROS), contributes to oxidative andvascular stress after glucose normalization and to developing and/ormaintaining the metabolic memory, and thus to the unifying link betweenhyperglycemia and cellular memory effects, such as e.g. in endothelialdysfunction or other complications of diabetes.

Thus, mainly related to persisting (long-term) oxidative stress inducedby or associated with (chronic, early or transient episodes of)hyperglycemia, there are certain metabolic conditions in that, evennormalizing glycemia, a long-term persitent activation of many pathwaysinvolved in the pathogenesis of diabetic complications can still bepresent. One of the major findings in the course of diabetes has therebybeen the demonstration that even in normoglycemia and independent of theactual glycemic levels an overproduction of free radicals can still beevident. For example, endothelial dysfunction (a causative marker ofdiabetic vascular complications) can persist even after normalizingglycemia. However, there is evidence that combining antioxidant therapywith normalization of glycemia can be used to almost interruptendothelial dysfunction.

Therefore, treating oxidative and/or vascular stress particularly beyondglycemic control, such as by the reduction of cellular reactive speciesand/or of glycation (e.g. by inhibition of the production of free oxygenand nitrogen radicals), preferably independently of glycemic status, maybeneficially modulate, reduce, block or protect against the memory'effect of hyperglycemia and reduce the risk, prevent, treat or delay theonset of long-term diabetic complications, particularly such ones whichare associated with or induced by oxidative stress, in patients in needthereof.

Standard therapy of type 1 diabetes is insulin treatment. Therapies fortype 1 diabetes are for example described in WO 2012/062698.

The treatment of type 2 diabetes typically begins with diet andexercise, followed by oral antidiabetic monotherapy, and althoughconventional monotherapy may initially control blood glucose in somepatients, it is however associated with a high secondary failure rate.The limitations of single-agent therapy for maintaining glycemic controlmay be overcome, at least in some patients, and for a limited period oftime by combining multiple drugs to achieve reductions in blood glucosethat cannot be sustained during long-term therapy with single agents.Available data support the conclusion that in most patients with type 2diabetes current monotherapy will fail and treatment with multiple drugswill be required. But, because type 2 diabetes is a progressive disease,even patients with good initial responses to conventional combinationtherapy will eventually require an increase of the dosage or furthertreatment with insulin because the blood glucose level is very difficultto maintain stable for a long period of time. Although existingcombination therapy has the potential to enhance glycemic control, it isnot without limitations (especially with regard to long term efficacy).Further, traditional therapies may show an increased risk for sideeffects, such as hypoglycemia or weight gain, which may compromise theirefficacy and acceptability.

Thus, for many patients, these existing drug therapies result inprogressive deterioriation in metabolic control despite treatment and donot sufficiently control metabolic status especially over long-term andthus fail to achieve and to maintain glycemic control in advanced orlate stage type 2 diabetes, including diabetes with inadequate glycemiccontrol despite conventional oral or non-oral antidiabetic medication.

Therefore, although intensive treatment of hyperglycemia can reduce theincidence of chronic damages, many patients with type 2 diabetes remaininadequately treated, partly because of limitations in long termefficacy, tolerability and dosing inconvenience of conventionalantihyperglycemic therapies.

This high incidence of therapeutic failure is a major contributor to thehigh rate of long-term hyperglycemia-associated complications or chronicdamages (including micro- and makrovascular complications such as e.g.diabetic nephrophathy, retinopathy or neuropathy, or cardiovascularcomplications such as e.g. myocardial infarction, stroke or vascularmortality or morbidity) in patients with type 2 diabetes.

Oral antidiabetic drugs conventionally used in therapy (such as e.g.first- or second-line, and/or mono- or (initial or add-on) combinationtherapy) include, without being restricted thereto, metformin,sulphonylureas, thiazolidinediones, DPP-4 inhibitors, glinides andα-glucosidase inhibitors.

Non-oral (typically injected) antidiabetic drugs conventionally used intherapy (such as e.g. first- or second-line, and/or mono- or (initial oradd-on) combination therapy) include, without being restricted thereto,GLP-1 or GLP-1 analogues, and insulin or insulin analogues.

However, the use of these conventional antidiabetic or antihyperglycemicagents can be associated with various adverse effects. For example,metformin can be associated with lactic acidosis or gastrointestinalside effects; sulfonylureas, glinides and insulin or insulin analoguescan be associated with hypoglycemia and weight gain; thiazolidinedionescan be associated with edema, bone fracture, weight gain and heartfailure/cardiac effects; and alpha-glucosidase blockers and GLP-1 orGLP-1 analogues can be associated with gastrointestinal adverse effects(e.g. dyspepsia, flatulence or diarrhea, or nausea or vomiting) and,most seriously (but rare), pancreatitis.

Therefore, it remains a need in the art to provide efficacious, safe andtolerable antidiabetic therapies.

Further, within the therapy of type 2 diabetes, it is a need fortreating the condition effectively, avoiding the complications inherentto the condition, and delaying disease progression, e.g. in order toachieve a long-lasting therapeutic benefit.

Furthermore, it remains a need that antidiabetic treatments not onlyprevent the long-term Moreover, it remains a need to provide preventionor reduction of risk for adverse effects associated with conventionalantidiabetic therapies.

SGLT2 inhibitors (sodium-glucose co-transporter 2) represent a novelclass of agents that are being developed for the treatment orimprovement in glycemic control in patients with type 2 diabetes.Glucopyranosyl-substituted benzene derivative are described as SGLT2inhibitors, for example in WO 01/27128, WO 03/099836, WO 2005/092877, WO2006/034489, WO 2006/064033, WO 2006/117359, WO 2006/117360, WO2007/025943, WO 2007/028814, WO 2007/031548, WO 2007/093610, WO2007/128749, WO 2008/049923, WO 2008/055870, WO 2008/055940. Theglucopyranosyl-substituted benzene derivatives are proposed as inducersof urinary sugar excretion and as medicaments in the treatment ofdiabetes.

Renal filtration and reuptake of glucose contributes, among othermechanisms, to the steady state plasma glucose concentration and cantherefore serve as an antidiabetic target. Reuptake of filtered glucoseacross epithelial cells of the kidney proceeds via sodium-dependentglucose cotransporters (SGLTs) located in the brush-border membranes inthe tubuli along the sodium gradient. There are at least 3 SGLT isoformsthat differ in their expression pattern as well as in theirphysico-chemical properties. SGLT2 is exclusively expressed in thekidney, whereas SGLT1 is expressed additionally in other tissues likeintestine, colon, skeletal and cardiac muscle. SGLT3 has been found tobe a glucose sensor in interstitial cells of the intestine without anytransport function. Potentially, other related, but not yetcharacterized genes, may contribute further to renal glucose reuptake.Under normoglycemia, glucose is completely reabsorbed by SGLTs in thekidney, whereas the reuptake capacity of the kidney is saturated atglucose concentrations higher than 10 mM, resulting in glucosuria(“diabetes mellitus”). This threshold concentration can be decreased bySGLT2-inhibition. It has been shown in experiments with the SGLTinhibitor phlorizin that SGLT-inhibition will partially inhibit thereuptake of glucose from the glomerular filtrate into the blood leadingto a decrease in blood glucose concentration and to glucosuria.

Empagliflozin is a novel SGLT2 inhibitor that is described for thetreatment or improvement in glycemic control in patients with type 2diabetes mellitus, for example in WO 05/092877, WO 06/117359, WO06/120208, WO 2010/092126, WO 2010/092123, WO 2011/039107, WO2011/039108.

Accordingly, in a particular embodiment, a SGLT-2 inhibitor within themeaning of this invention is empagliflozin.

Further, the present invention relates to a therapeutic (treatment orprevention) method as described herein, said method comprisingadministering an effective amount of a SGLT-2 inhibitor as describedherein and, optionally, one or more other active or therapeutic agentsas described herein to the patient in need thereof.

In one embodiment, diabetes patients within the meaning of thisinvention may include patients who have not previously been treated withan antidiabetic drug (drug-naïve patients). Thus, in an embodiment, thetherapies described herein may be used in naïve patients. In anotherembodiment, diabetes patients within the meaning of this invention mayinclude patients with advanced or late stage type 2 diabetes mellitus(including patients with failure to conventional antidiabetic therapy),such as e.g. patients with inadequate glycemic control on one, two ormore conventional oral and/or non-oral antidiabetic drugs as definedherein, such as e.g. patients with insufficient glycemic control despite(mono-)therapy with metformin, a thiazolidinedione (particularlypioglitazone), a sulphonylurea, a glinide, a DPP-4 inhibitor, GLP-1 orGLP-1 analogue, insulin or insulin analogue, or an α-glucosidaseinhibitor, or despite dual combination therapy withmetformin/sulphonylurea, metformin/thiazolidinedione (particularlypioglitazone), metformin/DPP-4 inhibitor, sulphonylurea/α-glucosidaseinhibitor, pioglitazone/sulphonylurea, metformin/insulin,pioglitazone/insulin or sulphonylurea/insulin. Thus, in an embodiment,the therapies described herein may be used in patients experienced withtherapy, e.g. with conventional oral and/or non-oral antidiabetic mono-or dual or triple combination medication as mentioned herein.

A further embodiment of diabetic patients within the meaning of thisinvention refers to type 1 or type 2 diabetes patients with or at riskof developping micro- or macrovascular diabetic complications, such ase.g. described herein (e.g. such at risk patients as described asfollows).

A further embodiment of the diabetes patients which may be amenable tothe therapies of this invention may include, without being limited,those type 1 or type 2 diabetes patients with or at risk of developpingretinal complications, such as diabetic retinopathy.

A further embodiment of the diabetes patients which may be amenable tothe therapies of this invention may include, without being limited,those type 1 or type 2 diabetes patients with or at risk of developpingmacrovascular complications, such as myocardial infarction, coronaryartery disease, ischemic or hemorrhagic stroke, and/or peripheralocclusive arterial disease.

A further embodiment of the diabetes patients which may be amenable tothe therapies of this invention may include, without being limited,those type 1 or type 2 diabetes patients with or at risk ofcardiovascular diseases or events (such as e.g. those cardiovascularrisk patients described herein).

A further embodiment of the diabetes patients which may be amenable tothe therapies of this invention may include, without being limited,those diabetes patients (especially type 2 diabetes) with advanced ageand/or with advanced diabetes disease, such as e.g. patients on insulintreatment, patients on triple antidiabetic oral therapy, patients withpre-existing cardiovascular events and/or patients with advanced diseaseduration (e.g. >/=5 to 10 years).

According to one aspect of the present invention a patient is a type 1or type 2 diabetes patient.

In one embodiment, the patient is a type 1 or type 2 diabetes patientwith one or more cardiovascular risk factors selected from A), B), C)and D):

A) previous or existing vascular disease selected from myocardialinfarction, coronary artery disease, percutaneous coronary intervention,coronary artery by-pass grafting, ischemic or hemorrhagic stroke,congestive heart failure, and peripheral occlusive arterial disease,B) advanced age >/=60-70 years, andC) one or more cardiovascular risk factors selected from

-   -   advanced type 2 diabetes mellitus >10 years duration,    -   hypertension,    -   current daily cigarette smoking,    -   dyslipidemia,    -   obesity,    -   age >/=40,    -   metabolic syndrome, hyperinsulinemia or insulin resistance, and    -   hyperuricemia, erectile dysfunction, polycystic ovary syndrome,        sleep apnea, or family history of vascular disease or        cardiomyopathy in first-degree relative;        D) one or more of the following:    -   confirmed history of myocardial infarction,    -   unstable angina with documented multivessel coronary disease or        positive stress test,    -   multivessel Percutaneous Coronary Intervention,    -   multivessel Coronary Artery By-pass Grafting (CABG),    -   history of ischemic or hemorrhagic stroke,    -   peripheral occlusive arterial disease.

In a further aspect of the present invention, a patient having at riskof a cardiovascular disease is defined as having at least one of thefollowing:

-   -   Confirmed history of myocardial infarction; or    -   Evidence of multivessel coronary artery disease, in 2 or more        major coronary arteries, irrespective of the revascularization        status, i.e.        -   a) Either the presence of a significant stenosis (imaging            evidence of at least 50% narrowing of the luminal diameter            measured during a coronary angiography or a multi-sliced            computed tomography angiography), in 2 or more major            coronary arteries,        -   b) Or a previous revascularisation (percutaneous            transluminal coronary angioplasty with or without stent, or            coronary artery bypass grafting), in 2 or more major            coronary arteries,        -   c) Or the combination of previous revascularisation in one            major coronary artery (percutaneous transluminal coronary            angioplasty with or without stent, or coronary artery bypass            grafting), and the presence of a significant stenosis in            another major coronary artery (imaging evidence of at least            50% narrowing of the luminal diameter measured during a            coronary angiography or a multi-sliced computed tomography            angiography),            -   Note: A disease affecting the left main coronary artery                is considered as a 2-vessel disease.    -   Evidence of a single vessel coronary artery disease with:        -   a) The presence of a significant stenosis i.e. the imaging            evidence of at least 50% narrowing of the luminal diameter            of one major coronary artery in patients not subsequently            successfully revascularised (measured during a coronary            angiography or a multi-sliced computed tomography            angiography)        -   b) And at least one of the following (either (i) or (ii)):            -   i. A positive non invasive stress test, confirmed by                either:                -   1. A positive exercise tolerance test in patients                    without a complete left bundle branch block,                    Wolff-Parkinson-White syndrome, or paced ventricular                    rhythm, or                -   2. A positive stress echocardiography showing                    regional systolic wall motion abnormalities, or                -   3. A positive scintigraphic test showing                    stress-induced ischemia, i.e. the development of                    transient perfusion defects during myocardial                    perfusion imaging;            -   ii. Or patient discharged from hospital with a                documented diagnosis of unstable angina within 12 months                prior to selection.    -   Episode of unstable angina with confirmed evidence of coronary        multivessel or single vessel disease as defined above.    -   History of ischemic or haemorrhagic stroke    -   Presence of peripheral artery disease (symptomatic or not)        documented by either: previous limb angioplasty, stenting or        bypass surgery; or previous limb or foot amputation due to        circulatory insufficiency; or angiographic evidence of        significant (>50%) peripheral artery stenosis in at least one        limb; or evidence from a non-invasive measurement of significant        (>50% or as reported as hemodynamically significant) peripheral        artery stenosis in at least one limb; or ankle brachial index of        <0.9 in at least one limb.

In a further aspect of the present invention, a patient having at riskof a cardiovascular disease is defined as having at least one of thefollowing:

-   -   a) Confirmed history of myocardial infarction,    -   b) Unstable angina with documented multivessel coronary disease        (at least two major coronary arteries in angiogram) or positive        stress test (ST segment depression >=2 mm or a positive nuclear        perfusion scintigram),    -   c) Multivessel Percutaneous Coronary Intervention (PCI),    -   d) Multivessel Coronary Artery By-pass Grafting (CABG),        including with recurrent angina following surgery,    -   e) History of ischemic or hemorrhagic stroke,    -   f) Peripheral occlusive arterial disease (previous limb bypass        surgery or percutaneous transluminal angioplasty; previous limb        or foot amputation due to circulatory insufficiency,        angiographic or imaging detected (for example: ultrasound,        Magnetic Resonance Imaging) significant vessel stenosis of major        limb arteries).

Moreover, the present invention relates to a certain SGLT-2 inhibitorfor use in a method of preventing, reducing the risk of or delaying theoccurrence of cardiovascular events, such as cardiovascular death,(fatal or non-fatal) myocardial infarction (e.g. silent or non-silentMI), (fatal or non-fatal) stroke, or hospitalisation (e.g. for acutecoronary syndrome, leg amputation, (urgent) revascularizationprocedures, heart failure or for unstable angina pectoris), preferablyin type 1 or type 2 diabetes patients, particularly in those type 1 ortype 2 diabetes patients being at risk of cardiovascular events, such astype 1 or type 2 diabetes patients with one or more risk factorsselected from A), B), C) and D):

A) previous or existing vascular disease (such as e.g. myocardialinfarction (e.g. silent or non-silent), coronary artery disease,percutaneous coronary intervention, coronary artery by-pass grafting,ischemic or hemorrhagic stroke, congestive heart failure (e.g. NYHAclass I, II, III or IV, e.g. left ventricular function <40%), orperipheral occlusive arterial disease),B) advanced age (such as e.g. age >/=60-70 years), andC) one or more cardiovascular risk factors selected from

-   -   advanced type 1 or type 2 diabetes mellitus (such as e.g. >10        years duration),    -   hypertension (such as e.g. >130/80 mm Hg, or systolic blood        pressure >140 mmHg or on at least one blood pressure lowering        treatment),    -   current daily cigarette smoking,    -   dyslipidemia (such as e.g. atherogenic dyslipidemia,        postprandial lipemia, or high level of LDL cholersterol (e.g.        LDL cholesterol >/=130-135 mg/dL), low level of HDL cholesterol        (e.g. <35-40 mg/dL in men or <45-50 mg/dL in women) and/or high        level of triglycerides (e.g. >200-400 mg/dL) in the blood, or on        at least one treatment for lipid abnormality),    -   obesity (such as e.g. abdominal and/or visceral obesity, or body        mass index >/=45 kg/m2),    -   age >/=40,    -   metabolic syndrome, hyperinsulinemia or insulin resistance, and    -   hyperuricemia, erectile dysfunction, polycystic ovary syndrome,        sleep apnea, or family history of vascular disease or        cardiomyopathy in first-degree relative,        D) one or more of the following:    -   confirmed history of myocardial infarction,    -   unstable angina with documented multivessel coronary disease or        positive stress test,    -   multivessel Percutaneous Coronary Intervention,    -   multivessel Coronary Artery By-pass Grafting (CABG),    -   history of ischemic or hemorrhagic stroke,    -   peripheral occlusive arterial disease,        said method comprising administering a therapeutically effective        amount of the SGLT-2 inhibitor, optionally in combination with        one or more other therapeutic substances, to the patient.

In a further aspect, the present invention relates to a certain SGLT-2inhibitor for use in a method of reducing arterial stiffness in apatient. In one aspect, the patient is a patient according to thepresent invention, in particular a patient with type 1 or type 2diabetes or pre-diabetes. Increased arterial stiffness is associatedwith an increased risk of cardiovascular events and the effect ofempagliflozin on arterial stiffness is for example shown in the Exampleshereinbelow.

The present invention further relates to a pharmaceutical compositioncomprising a certain SGLT-2 inhibitor as defined herein, empagliflozin,for use in the therapies described herein.

When this invention refers to patients requiring treatment orprevention, it relates primarily to treatment and prevention in humans,but the pharmaceutical composition may also be used accordingly inveterinary medicine in mammals. In the scope of this invention adultpatients are preferably humans of the age of 18 years or older. Also inthe scope of this invention, patients are adolescent humans, i.e. humansof age 10 to 17 years, preferably of age 13 to 17 years. It is assumedthat in a adolescent population the administration of the pharmaceuticalcomposition according to the invention a very good HbA1c lowering and avery good lowering of the fasting plasma glucose can be seen. Inaddition it is assumed that in an adolescent population, in particularin overweight and/or obese patients, a pronounced weight loss can beobserved.

As described hereinbefore by the administration of the pharmaceuticalcomposition according to this invention and in particular in view of thehigh SGLT2 inhibitory activity of the SGLT2 inhibitors therein,excessive blood glucose is excreted through the urine of the patient, sothat no gain in weight or even a reduction in body weight may result.Therefore, a treatment or prophylaxis according to this invention isadvantageously suitable in those patients in need of such treatment orprophylaxis who are diagnosed of one or more of the conditions selectedfrom the group consisting of overweight and obesity, in particular classI obesity, class II obesity, class III obesity, visceral obesity andabdominal obesity. In addition a treatment or prophylaxis according tothis invention is advantageously suitable in those patients in which aweight increase is contraindicated. The pharmaceutical composition aswell as the methods according to the present invention allow a reductionof the HbA1c value to a desired target range, for example <7% andpreferably <6.5%, for a higher number of patients and for a longer timeof therapeutic treatment compared with a corresponding monotherapy or atherapy using only two of the combination partners.

The pharmaceutical composition according to this invention and inparticular the SGLT2 inhibitor therein exhibits a very good efficacywith regard to glycemic control, in particular in view of a reduction offasting plasma glucose, postprandial plasma glucose and/or glycosylatedhemoglobin (HbA1c). By administering a pharmaceutical compositionaccording to this invention, a reduction of HbA1c equal to or greaterthan preferably 0.5%, even more preferably equal to or greater than 1.0%can be achieved and the reduction is particularly in the range from 1.0%to 2.0%.

Furthermore, the method and/or use according to this invention isadvantageously applicable in those patients who show one, two or more ofthe following conditions:

-   (a) a fasting blood glucose or serum glucose concentration greater    than 100 mg/dL, in particular greater than 125 mg/dL;-   (b) a postprandial plasma glucose equal to or greater than 140    mg/dL;-   (c) an HbA1c value equal to or greater than 6.5%, in particular    equal to or greater than 7.0%, especially equal to or greater than    7.5%, even more particularly equal to or greater than 8.0%.

The present invention also discloses the use of the pharmaceuticalcomposition for improving glycemic control in patients having type 1 ortype 2 diabetes or showing first signs of pre-diabetes. Thus, theinvention also includes diabetes prevention. If therefore apharmaceutical composition according to this invention is used toimprove the glycemic control as soon as one of the above-mentioned signsof pre-diabetes is present, the onset of manifest type 2 diabetesmellitus can be delayed or prevented.

Furthermore, the pharmaceutical composition according to this inventionis particularly suitable in the treatment of patients with insulindependency, i.e. in patients who are treated or otherwise would betreated or need treatment with an insulin or a derivative of insulin ora substitute of insulin or a formulation comprising an insulin or aderivative or substitute thereof. These patients include patients withdiabetes type 2 and patients with diabetes type 1.

Therefore, according to a preferred embodiment of the present invention,there is provided a method for improving glycemic control and/or forreducing of fasting plasma glucose, of postprandial plasma glucoseand/or of glycosylated hemoglobin HbA1c in a patient in need thereof whois diagnosed with impaired glucose tolerance (IGT), impaired fastingblood glucose (IFG) with insulin resistance, with metabolic syndromeand/or with type 2 or type 1 diabetes mellitus characterized in that anSGLT2 inhibitor as defined hereinbefore and hereinafter is administeredto the patient.

According to another preferred embodiment of the present invention,there is provided a method for improving gycemic control in patients, inparticular in adult patients, with type 2 diabetes mellitus as anadjunct to diet and exercise.

It can be found that by using a pharmaceutical composition according tothis invention, an improvement of the glycemic control can be achievedeven in those patients who have insufficient glycemic control inparticular despite treatment with an antidiabetic drug, for exampledespite maximal recommended or tolerated dose of oral monotherapy withmetformin. A maximal recommended dose with regard to metformin is forexample 2000 mg per day or 850 mg three times a day or any equivalentthereof.

Therefore, the method and/or use according to this invention isadvantageously applicable in those patients who show one, two or more ofthe following conditions:

-   (a) insufficient glycemic control with diet and exercise alone;-   (b) insufficient glycemic control despite oral monotherapy with    metformin, in particular despite oral monotherapy at a maximal    tolerated dose of metformin;-   (c) insufficient glycemic control despite oral monotherapy with    another antidiabetic agent, in particular despite oral monotherapy    at a maximal tolerated dose of the other antidiabetic agent.

The lowering of the blood glucose level by the administration of anSGLT2 inhibitor according to this invention is insulin-independent.Therefore, a pharmaceutical composition according to this invention isparticularly suitable in the treatment of patients who are diagnosedhaving one or more of the following conditions

-   -   insulin resistance,    -   hyperinsulinemia,    -   pre-diabetes,    -   type 2 diabetes mellitus, particular having a late stage type 2        diabetes mellitus,    -   type 1 diabetes mellitus.

Furthermore, a pharmaceutical composition according to this invention isparticularly suitable in the treatment of patients who are diagnosedhaving one or more of the following conditions

-   (a) obesity (including class I, II and/or III obesity), visceral    obesity and/or abdominal obesity,-   (b) triglyceride blood level 150 mg/dL,-   (c) HDL-cholesterol blood level <40 mg/dL in female patients and <50    mg/dL in male patients,-   (d) a systolic blood pressure 130 mm Hg and a diastolic blood    pressure 85 mm Hg,-   (e) a fasting blood glucose level 100 mg/dL.

It is assumed that patients diagnosed with impaired glucose tolerance(IGT), impaired fasting blood glucose (IFG), with insulin resistanceand/or with metabolic syndrome suffer from an increased risk ofdeveloping a cardiovascular disease, such as for example myocardialinfarction, coronary heart disease, heart insufficiency, thromboembolicevents. A glycemic control according to this invention may result in areduction of the cardiovascular risks.

Furthermore, a pharmaceutical composition according to this invention isparticularly suitable in the treatment of patients after organtransplantation, in particular those patients who are diagnosed havingone or more of the following conditions

-   (a) a higher age, in particular above 50 years,-   (b) male gender;-   (c) overweight, obesity (including class I, II and/or III obesity),    visceral obesity and/or abdominal obesity,-   (d) pre-transplant diabetes,-   (e) immunosuppression therapy.

Furthermore, a pharmaceutical composition according to this invention isparticularly suitable in the treatment of patients who are diagnosedhaving one or more of the following conditions:

(a) hyponatremia, in particular chronical hyponatremia;(b) water intoxication;(c) water retention;(d) plasma sodium concentration below 135 mmol/L.

The patient may be a diabetic or non-diabetic mammal, in particularhuman.

Furthermore, a pharmaceutical composition according to this invention isparticularly suitable in the treatment of patients who are diagnosedhaving one or more of the following conditions:

(a) high serum uric acid levels, in particular greater than 6.0 mg/dL(357 μmol/L);(b) a history of gouty arthritis, in particular recurrent goutyarthritis;(c) kidney stones, in particular recurrent kidney stones;(d) a high propensity for kidney stone formation.

In certain embodiments, the patients which may be amenable to to thetherapies of this invention may have or are at-risk of one or more ofthe following diseases, disorders or conditions: type 1 diabetes, type 2diabetes, impaired glucose tolerance (IGT), impaired fasting bloodglucose (IFG), hyperglycemia, postprandial hyperglycemia, postabsorptivehyperglycemia, latent autoimmune diabetes in adults (LADA), overweight,obesity, dyslipidemia, hyperlipidemia, hypercholesterolemia,hypertriglyceridemia, hyperNEFA-emia, postprandial lipemia,hypertension, atherosclerosis, endothelial dysfunction, osteoporosis,chronic systemic inflammation, non alcoholic fatty liver disease(NAFLD), polycystic ovarian syndrome, metabolic syndrome, nephropathy,micro- or macroalbuminuria, proteinuria, retinopathy, cataracts,neuropathy, learning or memory impairment, neurodegenerative orcognitive disorders, cardiovascular diseases, tissue ischaemia, diabeticfoot or ulcus, atherosclerosis, hypertension, endothelial dysfunction,myocardial infarction, acute coronary syndrome, unstable anginapectoris, stable angina pectoris, peripheral arterial occlusive disease,cardiomyopathy (including e.g. uremic cardiomyopathy), heart failure,cardiac hypertrophy, heart rhythm disorders, vascular restenosis,stroke, (renal, cardiac, cerebral or hepatic) ischemia/reperfusioninjuries, (renal, cardiac, cerebral or hepatic) fibrosis, (renal,cardiac, cerebral or hepatic) vascular remodeling; a diabetic disease,especially type 2 diabetes, mellitus may be preferred (e.g. asunderlying disease).

In a further embodiment, the patients which may be amenable to to thetherapies of this invention have a diabetic disease, especially type 2diabetes mellitus, and may have or are at-risk of one or more otherdiseases, disorders or conditions, such as e.g. selected from thosementioned immediately above.

In further embodiments, the present invention also relates to the effectof certain SGLT-2 inhibitors, in particular empagliflozin, on beta-cellsand/or on the function of beta-cells, for example in patients havinglatent autoimmune diabetes in adults (LADA).

Accordingly, in one embodiment, the present invention relates to certainSGLT-2 inhibitors, in particular empagliflozin, for use in preventing,slowing, delaying or treating the degeneration of pancreatic beta cellsand/or the decline of the functionality of pancreatic beta cells and/orfor improving and/or restoring the functionality of pancreatic betacells and/or restoring the functionality of pancreatic insulin secretionin a patient having latent autoimmune diabetes in adults (LADA).

In a further embodiment, the present invention relates to certain SGLT-2inhibitors, in particular empagliflozin, for use in preservingpancreatic beta cells and/or their function in a patient having latentautoimmune diabetes in adults (LADA).

In a further embodiment, the present invention relates to certain SGLT-2inhibitors, in particular empagliflozin, for use in stimulating and/orprotecting the functionality of pancreatic insulin secretion in apatient having latent autoimmune diabetes in adults (LADA).

Usually three criteria are needed fulfilled for diagnosis of LADA:

1) adult age at onset of diabetes (>30 years),2) the presence of circulating islet autoantibodies (markers of betacell autoimmunity to distinguish LADA from T2DM, e.g. islet cellantibodies (ICA, against cytoplasmic proteins in the beta cell,islet-cell cytoplasm), antibodies to glutamic acid decarboxylase(GAD-65, anti-GAD), insulin autoantibodies (IAA), and/or IA-2Aantibodies to the intracytoplasmatic domain of the tyrosinephosphatase-like protein IA-2), and3) lack of a requirement for insulin for at least 6 months afterdiagnosis (to distinguish LADA from classic T1 DM).

However, alternative definitions of LADA include GAD (glutamic aciddecarboxylase) antibody titer 0.08 U/mL and 1) lifestyle and oraltherapy or 2) insulin treatment started later than 12 months afterdiagnosis or 3) insulin therapy started before 12 months afterdiagnosis, but with fasting C-peptide levels >150 pmol/l.

C-peptide originates from proinsulin and is produced in the body alongwith insulin. It is an accepted biomarker for proof of beta-cellpreservation. Persons with LADA typically have low, although sometimesmoderate, levels of C-peptide as the disease progresses.

One prerequisite in the definition is the presence of one or morecirculating autoantibodies.

For this reasons it is sometimes argued that LADA is just a “low-titerT1 DM condition”.

However, the LADA population often shares phenotypical traits with T2DM,more so than with T1 DM; therefore LADA etiologically may represent aunique disease entity that is characterized by a more rapid decline ofn-cell function than common T2DM. It has been demonstrated, in severalstudies, that insulin dependency occurs at higher rate in LADA than insubjects with common T2DM.

Accordingly, in one aspect, a patient having LADA according to thepresent invention is a patient in whom one or more autoantibodiesselected from GAD (GAD-65, anti-GAD), ICA, IA-2A, ZnT8 (anti-ZnT8) andIAA are present, and in one aspect, in a method or use according to thepresent invention a patient having LADA is a patient in whom one or moreautoantibodies selected from GAD (GAD-65, anti-GAD), ICA, IA-2A, ZnT8(anti-ZnT8).

One assumes that the LADA prevalence in a general type 2 diabetespopulation is at least 5-10%. Moreover, adults with LADA are frequentlyinitially misdiagnosed as having type 2 diabetes, based on age; notetiology. In a survey conducted by Australia's Type 1 Diabetes

Network, one third of all Australians with type 1 diabetes reportedbeing initially misdiagnosed as having the more common type 2 diabetesmellitus.

Currently, there is no “gold standard” for LADA treatment or management.In general, the treatment of LADA should focus not only on controllingglycemia and preventing the onset of any complications, but also allowpreservation of residual beta cell function. Insulin therapy in LADA isoften efficacious; but might be of most benefit in patients with both ahigh titer of GAD (>10 U/mL) and preserved insulin secretion(C-peptide >10 ng/mL). This also seems to apply to thiazolidinediones(glitazones), in particular if combined with insulin when islet betacell function is preserved. Sulfonylureas (SUs) (and glinides) have insome studies been shown to be detrimental on beta cell function in LADA.This is supported by that metabolic control by SUs when compared toinsulin also is often less.

Accordingly, in a further embodiment, the present invention relates tocertain SGLT-2 inhibitors, in particular empagliflozin, for use intreating and/or preventing LADA (latent autoimmune diabetes of adults),particularly in those patients having LADA in whom one or moreautoantibodies selected from GAD (GAD-65, anti-GAD), ICA, IA-2A, ZnT8(anti-ZnT8) and IAA are present.

Within the scope of the present invention it has now been found thatcertain SGLT-2 inhibitors as defined herein, optionally in combinationwith one or more other therapeutic substances (e.g. selected from thosedescribed herein), as well as pharmaceutical combinations, compositionsor combined uses according to this invention of such SGLT-2 inhibitorsas defined herein have properties, which make them suitable for thepurpose of this invention and/or for fulfilling one or more of aboveneeds.

The effect of empagliflozin on cardiovascular diseases, in particular onthe risk of a cardiovascular event, for example such as defined herein,is for example determined as described in the Examples hereinbelow.

The effect of empagliflozin on beta-cells and/or on the function ofbeta-cells is for example determined as described in the Exampleshereinbelow.

The present invention thus relates to a certain SGLT-2 inhibitor asdefined herein, preferably empagliflozin, for use in the therapiesdescribed herein.

Furthermore, it can be found that the administration of a pharmaceuticalcomposition according to this invention results in no risk or in a lowrisk of hypoglycemia. Therefore, a treatment or prophylaxis according tothis invention is also advantageously possible in those patients showingor having an increased risk for hypoglycemia.

A pharmaceutical composition according to this invention is particularlysuitable in the long term treatment or prophylaxis of the diseasesand/or conditions as described hereinbefore and hereinafter, inparticular in the long term glycemic control in patients with type 2diabetes mellitus.

The term “long term” as used hereinbefore and hereinafter indicates atreatment of or administration in a patient within a period of timelonger than 12 weeks, preferably longer than 25 weeks, even morepreferably longer than 1 year.

Therefore, a particularly preferred embodiment of the present inventionprovides a method for therapy, preferably oral therapy, for improvement,especially long term improvement, of glycemic control in patients withtype 2 diabetes mellitus, especially in patients with late stage type 2diabetes mellitus, in particular in patients additionally diagnosed ofoverweight, obesity (including class I, class II and/or class IIIobesity), visceral obesity and/or abdominal obesity.

It will be appreciated that the amount of the pharmaceutical compositionaccording to this invention to be administered to the patient andrequired for use in treatment or prophylaxis according to the presentinvention will vary with the route of administration, the nature andseverity of the condition for which treatment or prophylaxis isrequired, the age, weight and condition of the patient, concomitantmedication and will be ultimately at the discretion of the attendantphysician. In general, however, the SGLT2 inhibitor according to thisinvention is included in the pharmaceutical composition or dosage formin an amount sufficient that by its administration the glycemic controlin the patient to be treated is improved.

For the treatment of hyperuricemia or hyperuricemia associatedconditions the SGLT2 inhibitor according to this invention is includedin the pharmaceutical composition or dosage form in an amount sufficientthat is sufficient to treat hyperuricemia without disturbing thepatient's plasma glucose homeostasis, in particular without inducinghypoglycemia.

For the treatment or prevention of kidney stones the SGLT2 inhibitoraccording to this invention is included in the pharmaceuticalcomposition or dosage form in an amount sufficient that is sufficient totreat or prevent kidney stones without disturbing the patient's plasmaglucose homeostasis, in particular without inducing hypoglycemia.

For the treatment of hyponatremia and associated conditions the SGLT2inhibitor according to this invention is included in the pharmaceuticalcomposition or dosage form in an amount sufficient that is sufficient totreat hyponatremia or the associated conditions without disturbing thepatient's plasma glucose homeostasis, in particular without inducinghypoglycemia.

In the following preferred ranges of the amount of the SGLT2 inhibitorto be employed in the pharmaceutical composition and the methods anduses according to this invention are described. These ranges refer tothe amounts to be administered per day with respect to an adult patient,in particular to a human being, for example of approximately 70 kg bodyweight, and can be adapted accordingly with regard to an administration2, 3, 4 or more times daily and with regard to other routes ofadministration and with regard to the age of the patient. Within thescope of the present invention, the pharmaceutical composition ispreferably administered orally. Other forms of administration arepossible and described hereinafter. Preferably the one or more dosageforms comprising the SGLT2 inhibitor is oral or usually well known.

In general, the amount of the SGLT2 inhibitor in the pharmaceuticalcomposition and methods according to this invention is preferably theamount usually recommended for a monotherapy using said SGLT2 inhibitor.

The preferred dosage range of the SGLT2 inhibitor is in the range from0.5 mg to 200 mg, even more preferably from 1 to 100 mg, most preferablyfrom 1 to 50 mg per day. In one aspect, a preferred dosage of the SGLT2inhibitor empagliflozin is 10 mg or 25 mg per day. The oraladministration is preferred. Therefore, a pharmaceutical composition maycomprise the hereinbefore mentioned amounts, in particular from 1 to 50mg or 1 to 25 mg. Particular dosage strengths (e.g. per tablet orcapsule) are for example 1, 2.5, 5, 7.5, 10, 12.5, 15, 20, or 50 mg ofthe SGLT2 inhibitor, in particular empagliflozin. In one aspect, apharmaceutical composition comprises 10 mg or 25 mg of empagliflozin.The application of the active ingredient may occur up to three times aday, preferably one or two times a day, most preferably once a day.

A pharmaceutical composition which is present as a separate or multipledosage form, preferably as a kit of parts, is useful in combinationtherapy to flexibly suit the individual therapeutic needs of thepatient.

According to a first embodiment a preferred kit of parts comprises acontainment containing a dosage form comprising the SGLT2 inhibitor andat least one pharmaceutically acceptable carrier.

A further aspect of the present invention is a manufacture comprisingthe pharmaceutical composition being present as separate dosage formsaccording to the present invention and a label or package insertcomprising instructions that the separate dosage forms are to beadministered in combination or alternation.

According to a first embodiment a manufacture comprises (a) apharmaceutical composition comprising a SGLT2 inhibitor according to thepresent invention and (b) a label or package insert which comprisesinstructions that the medicament is to be administered.

The desired dose of the pharmaceutical composition according to thisinvention may conveniently be presented in a once daily or as divideddose administered at appropriate intervals, for example as two, three ormore doses per day.

The pharmaceutical composition may be formulated for oral, rectal,nasal, topical (including buccal and sublingual), transdermal, vaginalor parenteral (including intramuscular, sub-cutaneous and intravenous)administration in liquid or solid form or in a form suitable foradministration by inhalation or insufflation. Oral administration ispreferred. The formulations may, where appropriate, be convenientlypresented in discrete dosage units and may be prepared by any of themethods well known in the art of pharmacy. All methods include the stepof bringing into association the active ingredient with one or morepharmaceutically acceptable carriers, like liquid carriers or finelydivided solid carriers or both, and then, if necessary, shaping theproduct into the desired formulation.

The pharmaceutical composition may be formulated in the form of tablets,granules, fine granules, powders, capsules, caplets, soft capsules,pills, oral solutions, syrups, dry syrups, chewable tablets, troches,effervescent tablets, drops, suspension, fast dissolving tablets, oralfast-dispersing tablets, etc.

The pharmaceutical composition and the dosage forms preferably comprisesone or more pharmaceutical acceptable carriers which must be“acceptable” in the sense of being compatible with the other ingredientsof the formulation and not deleterious to the recipient thereof.Examples of pharmaceutically acceptable carriers are known to the oneskilled in the art.

Pharmaceutical compositions suitable for oral administration mayconveniently be presented as discrete units such as capsules, includingsoft gelatin capsules, cachets or tablets each containing apredetermined amount of the active ingredient; as a powder or granules;as a solution, a suspension or as an emulsion, for example as syrups,elixirs or self-emulsifying delivery systems (SEDDS). The activeingredients may also be presented as a bolus, electuary or paste.Tablets and capsules for oral administration may contain conventionalexcipients such as binding agents, fillers, lubricants, disintegrants,or wetting agents. The tablets may be coated according to methods wellknown in the art. Oral liquid preparations may be in the form of, forexample, aqueous or oily suspensions, solutions, emulsions, syrups orelixirs, or may be presented as a dry product for constitution withwater or other suitable vehicle before use. Such liquid preparations maycontain conventional additives such as suspending agents, emulsifyingagents, non-aqueous vehicles (which may include edible oils), orpreservatives.

The pharmaceutical composition according to the invention may also beformulated for parenteral administration (e.g. by injection, for examplebolus injection or continuous infusion) and may be presented in unitdose form in ampoules, pre-filled syringes, small volume infusion or inmulti-dose containers with an added preservative. The compositions maytake such forms as suspensions, solutions, or emulsions in oily oraqueous vehicles, and may contain formulatory agents such as suspending,stabilizing and/or dispersing agents. Alternatively, the activeingredients may be in powder form, obtained by aseptic isolation ofsterile solid or by lyophilisation from solution, for constitution witha suitable vehicle, e.g. sterile, pyrogen-free water, before use.

Pharmaceutical compositions suitable for rectal administration whereinthe carrier is a solid are most preferably presented as unit dosesuppositories. Suitable carriers include cocoa butter and othermaterials commonly used in the art, and the suppositories may beconveniently formed by admixture of the active compound(s) with thesoftened or melted carrier(s) followed by chilling and shaping inmoulds.

The pharmaceutical compositions and methods according to this inventionshow advantageous effects in the treatment and prevention of thosediseases and conditions as described hereinbefore. Advantageous effectsmay be seen for example with respect to efficacy, dosage strength,dosage frequency, pharmacodynamic properties, pharmacokineticproperties, fewer adverse effects, convenience, compliance, etc.

Methods for the manufacture of SGLT2 inhibitors according to thisinvention and of prodrugs thereof are known to the one skilled in theart. Advantageously, the compounds according to this invention can beprepared using synthetic methods as described in the literature,including patent applications as cited hereinbefore. Preferred methodsof manufacture are described in the WO 2006/120208 and WO 2007/031548.With regard to empagliflozin an advantageous crystalline form isdescribed in the international patent application WO 2006/117359 whichhereby is incorporated herein in its entirety.

The active ingredients may be present in the form of a pharmaceuticallyacceptable salt. Pharmaceutically acceptable salts include, withoutbeing restricted thereto, such as salts of inorganic acid likehydrochloric acid, sulfuric acid and phosphoric acid; salts of organiccarboxylic acid like oxalic acid, acetic acid, citric acid, malic acid,benzoic acid, maleic acid, fumaric acid, tartaric acid, succinic acidand glutamic acid and salts of organic sulfonic acid likemethanesulfonic acid and p-toluenesulfonic acid. The salts can be formedby combining the compound and an acid in the appropriate amount andratio in a solvent and decomposer. They can be also obtained by thecation or anion exchange from the form of other salts.

The active ingredients or a pharmaceutically acceptable salt thereof maybe present in the form of a solvate such as a hydrate or alcohol adduct.

Pharmaceutical compositions or combinations for use in these therapiescomprising the SGLT-2 inhibitor as defined herein optionally togetherwith one or more other active substances are also contemplated.

Further, the present invention relates to the SGLT-2 inhibitors,optionally in combination with one, two or more further active agents,each as defined herein, for use in the therapies as described herein.

Further, the present invention relates to the use of the SGLT-2inhibitors, optionally in combination with one, two or more furtheractive agents, each as defined herein, for preparing pharmaceuticalcompositions which are suitable for the treatment and/or preventionpurposes of this invention.

The present invention further relates to a pharmaceutical compositioncomprising a certain SGLT-2 inhibitor as defined herein, preferablyempagliflozin, and metformin, for use in the therapies described herein.

The present invention further relates to a combination comprising acertain SGLT-2 inhibitor (particularly empagliflozin) and one or moreother active substances selected from those mentioned herein, e.g.selected from other antidiabetic substances, active substances thatlower the blood sugar level, active substances that lower the lipidlevel in the blood, active substances that raise the HDL level in theblood, active substances that lower blood pressure, active substancesthat are indicated in the treatment of atherosclerosis or obesity,antiplatelet agents, anticoagulant agents, and vascular endothelialprotective agents, e.g. each as described herein; particularly forsimultaneous, separate or sequential use in the therapies describedherein.

The present invention further relates to a combination comprising acertain SGLT-2 inhibitor (particularly empagliflozin) and one or moreother antidiabetics selected from the group consisting of metformin, asulphonylurea, nateglinide, repaglinide, a thiazolidinedione, aPPAR-gamma-agonist, an alpha-glucosidase inhibitor, insulin or aninsulin analogue, GLP-1 or a GLP-1 analogue and a DPP-4 inhibitor,particularly for simultaneous, separate or sequential use in thetherapies described herein.

The present invention further relates to a method for treating and/orpreventing metabolic disorders, especially type 2 diabetes mellitusand/or conditions related thereto (e.g. diabetic complications)comprising the combined (e.g. simultaneous, separate or sequential)administration of an effective amount of one or more other antidiabeticsselected from the group consisting of metformin, a sulphonylurea,nateglinide, repaglinide, a PPAR-gamma-agonist, an alpha-glucosidaseinhibitor, insulin or an insulin analogue, GLP-1 or a GLP-1 analogue anda DPP-4 inhibitor, to the patient (particularly human patient) in needthereof, such as e.g. a patient as described herein, including at-riskpatient groups.

The present invention further relates to therapies or therapeuticmethods described herein, such as e.g. a method for treating and/orpreventing metabolic disorders, especially type 2 diabetes mellitusand/or conditions related thereto (e.g. diabetic complications),comprising administering a therapeutically effective amount ofempagliflozin and, optionally, one or more other therapeutic agents,such as e.g. antidiabetics selected from the group consisting ofmetformin, a sulphonylurea, nateglinide, repaglinide, aPPAR-gamma-agonist, an alpha-glucosidase inhibitor, insulin or aninsulin analogue, GLP-1 or a GLP-1 analogue and a DPP-4 inhibitor, tothe patient (particularly human patient) in need thereof, such as e.g. apatient as described herein (e.g. at-risk patient as described herein).

Within this invention it is to be understood that the combinations,compositions or combined uses according to this invention may envisagethe simultaneous, sequential or separate administration of the activecomponents or ingredients.

In this context, “combination” or “combined” within the meaning of thisinvention may include, without being limited, fixed and non-fixed (e.g.free) forms (including kits) and uses, such as e.g. the simultaneous,sequential or separate use of the components or ingredients.

The combined administration of this invention may take place byadministering the active components or ingredients together, such ase.g. by administering them simultaneously in one single or in twoseparate formulations or dosage forms. Alternatively, the administrationmay take place by administering the active components or ingredientssequentially, such as e.g. successively in two separate formulations ordosage forms.

For the combination therapy of this invention the active components oringredients may be administered separately (which implies that they areformulated separately) or formulated altogether (which implies that theyare formulated in the same preparation or in the same dosage form).Hence, the administration of one element of the combination of thepresent invention may be prior to, concurrent to, or subsequent to theadministration of the other element of the combination.

Unless otherwise noted, combination therapy may refer to first line,second line or third line therapy, or initial or add-on combinationtherapy or replacement therapy.

The present invention further relates to a certain SGLT-2 inhibitor asdefined herein, preferably empagliflozin, in combination with metformin,for use in the therapies described herein.

Metformin is usually given in doses varying from about 500 mg to 2000 mgup to 2500 mg per day using various dosing regimens from about 100 mg to500 mg or 200 mg to 850 mg (1-3 times a day), or about 300 mg to 1000 mgonce or twice a day, or delayed-release metformin in doses of about 100mg to 1000 mg or preferably 500 mg to 1000 mg once or twice a day orabout 500 mg to 2000 mg once a day. Particular dosage strengths may be250, 500, 625, 750, 850 and 1000 mg of metformin hydrochloride.

For children 10 to 16 years of age, the recommended starting dose ofmetformin is 500 mg given once daily. If this dose fails to produceadequate results, the dose may be increased to 500 mg twice daily.Further increases may be made in increments of 500 mg weekly to amaximum daily dose of 2000 mg, given in divided doses (e.g. 2 or 3divided doses). Metformin may be administered with food to decreasenausea.

An example of a DPP-4 inhibitor is linagliptin, which is usually givenin a dosage of 5 mg per day.

A dosage of pioglitazone is usually of about 1-10 mg, 15 mg, 30 mg, or45 mg once a day.

Rosiglitazone is usually given in doses from 4 to 8 mg once (or dividedtwice) a day (typical dosage strengths are 2, 4 and 8 mg).

Glibenclamide (glyburide) is usually given in doses from 2.5-5 to 20 mgonce (or divided twice) a day (typical dosage strengths are 1.25, 2.5and 5 mg), or micronized glibenclamide in doses from 0.75-3 to 12 mgonce (or divided twice) a day (typical dosage strengths are 1.5, 3, 4.5and 6 mg).

Glipizide is usually given in doses from 2.5 to 10-20 mg once (or up to40 mg divided twice) a day (typical dosage strengths are 5 and 10 mg),or extended-release glibenclamide in doses from 5 to 10 mg (up to 20 mg)once a day (typical dosage strengths are 2.5, 5 and 10 mg).

Glimepiride is usually given in doses from 1-2 to 4 mg (up to 8 mg) oncea day (typical dosage strengths are 1, 2 and 4 mg).

The non-sulphonylurea insulin secretagogue nateglinide is usually givenin doses from 60 to 120 mg with meals (up to 360 mg/day, typical dosagestrengths are 60 and 120 mg); repaglinide is usually given in doses from0.5 to 4 mg with meals (up to 16 mg/day, typical dosage strengths are0.5, 1 and 2 mg). A dual combination of repaglinide/metformin isavailable in dosage strengths of 1/500 and 2/850 mg.

In one aspect of the present invention, the one or more othertherapeutic substances are active substances that lower the blood sugarlevel, active substances that lower the lipid level in the blood, activesubstances that raise the HDL level in the blood, active substances thatlower blood pressure, active substances that are indicated in thetreatment of atherosclerosis or obesity, antiplatelet agents,anticoagulant agents, and vascular endothelial protective agents.

In one aspect, the present invention provides a method of treatmentcomprising identifying a patient with type 2 diabetes treated with aplurality of medications to treat a cardiovascular disease,administering empagliflozin to said patient; and reducing the number,dosage or regimen of medications to treat a cardiovascular disease insaid patient, in particular while continuing to administer empagliflozinto the patient. In one embodiment, the method further comprisesmonitoring the cardiac health of said patient.

Examples of medications to treat a cardiovascular disease includemedications that lower blood, such as for example beta-blockers,diuretics, calcium channel blockers, Angiotensin-Converting Enzyme (ACE)inhibitors and angiotensin II receptor blockers (ARBs).

Examples of medications that lower blood pressure are beta-blockers suchas acebutolol, atenolol, Betaxolol, bisoprolol, celiprolol, metoprolol,nebivolol, Propranolol, Timolol and carvedilol; the dosage(s) of some ofthese medications are for example shown below:

-   -   Acebutolol (Sectral), 200 or 400 mg of acebutolol as the        hydrochloride salt    -   Atenolol (Tenormin), 25, 50 and 100 mg tablets for oral        administration    -   Betaxolol (Kerlone), 10-mg and 20-mg tablets for oral        administration    -   Bisoprolol/hydrochlorothiazide (Ziac), 2.5/6 mg, 5/6.25 mg,        10/6.25 mg    -   Bisoprolol (Zebeta), 5 and 10 mg tablets for oral administration    -   Metoprolol (Lopressor, Toprol XL), 50- and 100-mg tablets for        oral administration and in 5-mL ampuls for intravenous        administration    -   Propranolol (Inderal), 10 mg, 20 mg, 40 mg, 60 mg, and 80 mg        tablets for oral administration    -   Timolol (Blocadren), 5 mg, 10 mg or 20 mg timolol maleate for        oral administration.

Examples of medications that lower blood pressure are diuretics such asBumetanide, hydrochlorothiazide, chlortalidon, Chlorothiazide,Hydro-chlorothiazide, xipamide, Indapamide, furosemide, piretanide,torasemide, spironolactone, eplerenone, am iloride and triamterene; forexample these medications are thiazide diuretics, eg chlorthalidone,HCT, loop diuretics, eg furosemide, torasemide or potassium-sparingdiuretics, eg eplerenone, or combination thereof; the dosage(s) of someof these medications are for example shown below:

-   -   Amiloride (Midamor), 5 mg of anhydrous amiloride HCl    -   Bumetanide (Bumex), available as scored tablets, 0.5 mg (light        green), 1 mg (yellow) and 2 mg (peach) for oral administration    -   Chlorothiazide (Diuril),    -   Chlorthalidone (Hygroton)    -   Furosemide (Lasix)    -   Hydro-chlorothiazide (Esidrix, Hydrodiuril)    -   Indapamide (Lozol) and Spironolactone (Aldactone)    -   Eplerenone (Inspra)

Examples of medications that lower blood pressure are calcium channelblockers such as amlodipine, nifedipine, nitrendipine, nisoldipine,nicardipine, felodipine, lacidipine, lercanipidine, manidipine,isradipine, nilvadipine, verapamil, gallopamil and diltiazem.

Examples of medications that lower blood pressure areAngiotensin-Converting Enzyme (ACE) inhibitors such as Benazepril,Captopril, ramipril, lisinopril, Moexipril, cilazapril, quinapril,captopril, enalapril, benazepril, perindopril, fosinopril andtrandolapril; the dosage(s) of some of these medications are for exampleshown below:

-   -   Benazepril (Lotensin), 5 mg, 10 mg, 20 mg, and 40 mg for oral        administration    -   Captopril (Capoten), 12.5 mg, 25 mg, 50 mg, and 100 mg as scored        tablets for oral administration    -   Enalapril (Vasotec), 2.5 mg, 5 mg, 10 mg, and 20 mg tablets for        oral administration    -   Fosinopril (Monopril), for oral administration as 10 mg, 20 mg,        and 40 mg tablets    -   Lisinopril (Prinivil, Zestril), 5 mg, 10 mg, and 20 mg tablets        for oral administration    -   Moexipril (Univasc), 7.5 mg and 15 mg for oral administration    -   Perindopril (Aceon), 2 mg, 4 mg and 8 mg strengths for oral        administration    -   Quinapril (Accupril), 5 mg, 10 mg, 20 mg, or 40 mg of quinapril        for oral administration    -   Ramipril (Altace), 1.25 mg, 2.5 mg, 5, mg, 10 mg    -   Trandolapril (Mavik), 1 mg, 2 mg, or 4 mg of trandolapril for        oral administration

Examples of medications that lower blood pressure are angiotensin IIreceptor blockers (ARBs) such as telmisartan, candesartan, valsartan,losartan, irbesartan, olmesartan, azilsartan and eprosartan; thedosage(s) of some of these medications are for example shown below:

-   -   Candesartan (Atacand), 4 mg, 8 mg, 16 mg, or 32 mg of        candesartan cilexetil    -   Eprosartan (Teveten), 400 mg or 600 mg    -   Irbesartan (Avapro), 75 mg, 150 mg, or 300 mg of irbesartan.    -   Losartan (Cozaar), 25 mg, 50 mg or 100 mg of losartan potassium    -   Telmisartan (Micardis), 40 mg/12.5 mg, 80 mg/12.5 mg, and 80        mg/25 mg telmisartan and hydrochlorothiazide    -   Valsartan (Diovan), 40 mg, 80 mg, 160 mg or 320 mg of valsartan

A dosage of telmisartan is usually from 20 mg to 320 mg or 40 mg to 160mg per day.

Further embodiments, features and advantages of the present inventionmay become apparent from the following examples. The following examplesserve to illustrate, by way of example, the principles of the inventionwithout restricting it.

EXAMPLES Example 1 Effects of SGLT2 Inhibition on Oxidative Stress,Vessel Wall Thickness and Collagen Content, and Endothelial Dysfunctionin STZ-Induced Diabetes Mellitus (Type I) in Rat

Type I diabetes in Wistar rats (8 weeks old, 250-300 g) are induced by asingle i.v. injection of STZ (60 mg/kg). The blood glucose level ismeasured 3 days after STZ injection (to test whether diabetes wasinduced) and on the day of sacrifice. One week after injectionempagliflozin (SGLT2-i) was administered with drinking water foradditional 7 weeks (10 and 30 mg/kg/d p.o.). Treatment withempagliflozin showed a distinct reduction of blood glucose levels indiabetic rats without influence on loss of weight gain. Isometrictension recordings showed an empagliflozin-dependent normalization ofendothelial function in diabetic animals and reduced oxidative stress inaortic vessels and blood, examined by DHE staining of aorticcryosections and PDBu/zymosanA-stimulated chemiluminescence,respectively. Additionally, a tendency of increased NADPH-oxidaseactivity in heart and a significant reduction of ALDH-2 activity in theliver were observed in diabetic animals, reflecting oxidative stressdiminution triggered by empagliflozin therapy. The results are shown inFIGS. 1-13.

FIG. 1A-C: Shows the effect of Empagliflozin on weight gain, bloodglucose and glycated hemoglobin (HbA1C) at low dose (10 mg/kg) and highdose (30 mg/kg) given in drinking water.

FIG. 2: A: Endothelial dependant vasorelaxation. This figure shows theimprovement of endothelial function measured with isolated aortic ringsafter 7 weeks of treatment. B: Endothelial independent vasorelaxationobtain with glyceryl trinitrate (GTN) a NO donor. This figure shows thecapacity of all vessel walls to vasorelax independantly of theendothelium demonstrating the absence of deleterious effect of thetreament on smooth muscle cells.

FIGS. 3-9: Quantification of reactive oxygen species of (ROS) fromleukocyte upon stimulation with zymosan A (ZymA). After 7 weeks oftreament, ROS production in blood is reduced either with the low or highdose of empagliflozin to level close to none diabetic animal.

FIG. 10: Shows that the NADPH oxidase activity in the cardiac tissue, animportant source of superoxide is diminished with empagliflozintreatment.

FIG. 11: Shows that the reduction of ALDH-2 activity in diabetic STZanimal is partly restored with empagliflozin treatment.

FIGS. 12A and 12B: Shows that the superoxide formation in the vessels ofdiabetic animals is reduced. FIG. 12A shows results with a partial setof animals, FIG. 12B shows results with all animals.

FIG. 13A-D: Shows the level of plasmatic cholesterol, triglycerides,insulin and Interferon γ in STZ diabetic rats compared to normal rat andin diabetic rat treated with empagliflozin.

While empagliflozin restore insulin level, the elevation of interferon γ(a marker of inflammation) in diabetic rats is highly diminished orsupressed with empagliflozin treatment.

Aortic wall thickness and collagen content were also measuredmicroscopically after sirius red staining. Aortic segments were fixed inparafomaldehyde (4%) and paraffin-embedded. Sirius red staining forvascular fibrosis was performed with paraffin-embedded samples of aortictissue upon de-paraffination. Afterwards the nuclei were prestained withhemalum. Then samples were stained for 1 hour in 0.1% with Sirius redsolution containing saturated picric acid (1.2%). Finally, tissuesamples were dehydrated with 70%, 96% and 100% isopropanol andcoverslipped with a solution of polymers in xylene. 60-70 measurementswere made per sample, n=6-7 animals/groups. The results are shown inFIGS. 16A and 16B.

FIGS. 16A and 16B: Microscopic determination of aortic wall thicknessand collagen content by sirius red staining of aortic paraffinatedsections. Quantification (FIG. 16A) and representative microscope images(FIG. 16B). Aortic wall thickness and collagen content was slightlyincreased in diabetic rats and was normalized by empagliflozintreatment.

Example 2 Measurement of Hourly Blood Pressure

Empagliflozin (10 mg and 25 mg) was administered orally once daily over12 weeks in hypertensive patients with type 2 diabetes mellitus. Thechange from baseline in hourly mean systolic blood pressure (SBP) anddiastolic blood pressure (DBP) was measured over a 24-hour period afer12 weeks of treatment compared to the placebo group and is shown inFIGS. 14 and 15.

Example 3 Treatment of Patients with Type 2 Diabetes Mellitus withElevated Cardiovascular Risk

The longterm impact on cardiovascular morbidity and mortality andrelevant efficacy parameters (e.g. HbA1c, fasting plasma glucose,treatment sustainability) of treatment with empagliflozin in a relevantpopulation of patients with type 2 diabetes mellitus is investigated asfollows:

Type 2 diabetes patient with elevated risk of cardiovascular events,e.g. as defined below, are treated over a lengthy period (e.g. forbetween approximately 6 and 8 years) with empagliflozin (optionally incombination with one or more other active substances, e.g. such as thosedescribed herein) and compared with patients who have been treated witha placebo on standard of care background medication.

Empagliflozin is administered orally once daily (10 mg/daily or 25mg/daily). Patients are diagnosed with type 2 diabetes mellitus, are ondiet and exercise regimen and are drug-naïve or pre-treated with anybackground therapy. Patients have a HbA_(1c) of 7.0% and 10% forpatients on background therapy or HbA_(1c)≧7.0% and 9.0% for drug-naïvepatients. Patients with an elevated cardiovascular risk are defined ashaving at least one of the following:

-   -   Confirmed history of myocardial infarction; or    -   Evidence of multivessel coronary artery disease, in 2 or more        major coronary arteries, irrespective of the revascularization        status, i.e.        -   a) Either the presence of a significant stenosis (imaging            evidence of at least 50% narrowing of the luminal diameter            measured during a coronary angiography or a multi-sliced            computed tomography angiography), in 2 or more major            coronary arteries,        -   b) Or a previous revascularisation (percutaneous            transluminal coronary angioplasty with or without stent, or            coronary artery bypass grafting), in 2 or more major            coronary arteries,        -   c) Or the combination of previous revascularisation in one            major coronary artery (percutaneous transluminal coronary            angioplasty with or without stent, or coronary artery bypass            grafting), and the presence of a significant stenosis in            another major coronary artery (imaging evidence of at least            50% narrowing of the luminal diameter measured during a            coronary angiography or a multi-sliced computed tomography            angiography),            -   Note: A disease affecting the left main coronary artery                is considered as a 2-vessel disease.    -   Evidence of a single vessel coronary artery disease with:        -   a) The presence of a significant stenosis i.e. the imaging            evidence of at least 50% narrowing of the luminal diameter            of one major coronary artery in patients not subsequently            successfully revascularised (measured during a coronary            angiography or a multi-sliced computed tomography            angiography)        -   b) And at least one of the following (either (i) or (ii)):            -   i. A positive non invasive stress test, confirmed by                either:                -   1. A positive exercise tolerance test in patients                    without a complete left bundle branch block,                    Wolff-Parkinson-White syndrome, or paced ventricular                    rhythm, or                -   2. A positive stress echocardiography showing                    regional systolic wall motion abnormalities, or                -   3. A positive scintigraphic test showing                    stress-induced ischemia, i.e. the development of                    transient perfusion defects during myocardial                    perfusion imaging;            -   ii. Or patient discharged from hospital with a                documented diagnosis of unstable angina within 12 months                prior to selection.    -   Episode of unstable angina with confirmed evidence of coronary        multivessel or single vessel disease as defined above.    -   History of ischemic or haemorrhagic stroke    -   Presence of peripheral artery disease (symptomatic or not)        documented by either: previous limb angioplasty, stenting or        bypass surgery; or previous limb or foot amputation due to        circulatory insufficiency; or angiographic evidence of        significant (>50%) peripheral artery stenosis in at least one        limb; or evidence from a non-invasive measurement of significant        (>50% or as reported as hemodynamically significant) peripheral        artery stenosis in at least one limb; or ankle brachial index of        <0.9 in at least one limb.

Criteria for efficacy are for example change from baseline in: HbA1c,Fasting Plasma Glucose (FPG), weight, waist circumference and bloodpressure at weeks 12, 52, once a year, and end of study.

The time to first occurrence of any of the adjudicated components of theprimary composite Major Adverse Cardiovascular Event (MACE) endpoint(cardiovascular death (including fatal stroke and fatal myocardialinfarction), non fatal stroke, nonfatal myocardial infarction (MI) isdetermined in patients treated with empagliflozin compared to placebo.

The time to the first occurrence of the following adjudicated events(treated as a composite): CV death (including fatal stroke and fatalMI), non-fatal MI (excluding silent MI), non-fatal stroke andhospitalization for unstable angina pectoris is also determined inpatients treated with empagliflozin compared to placebo.

Also determined are the occurrence of and time to each of the followingevents:

-   -   Silent MI.    -   Heart failure requiring hospitalization    -   New onset albuminuria defined as ACR 30 mg/g    -   New onset macroalbuminuria 300 mg/g.    -   Composite microvascular outcome defined as:        -   1) Need for retinal photocoagulation        -   2) Vitreous haemorrhage        -   3) Diabetes-related blindness        -   4) New or worsening nephropathy defined as:            -   4a) New onset of macroalbuminuria; or 4b) Doubling of                serum creatinine level accompanied by an eGFR (based on                modification of diet in renal disease (MDRD) formula) 45                mL/min/1.73 m²; or 4c) Need for continuous renal                replacement therapy; or d) death due to renal disease.

Also determined are the occurrence of and time to each of the followingadjudicated events:

-   -   CV death (including fatal stroke and fatal MI)    -   non-fatal MI    -   non-fatal stroke    -   Hospitalization for unstable angina    -   All cause mortality    -   TIA    -   coronary revascularization procedures.

Example 4 Treatment of Type 2 Diabetes Mellitus

Treating patients with type 2 diabetes mellitus with empagliflozin, inaddition to producing an acute improvement in the glucose metabolicsituation, prevents a deterioration in the metabolic situation in thelong term. This can be observed is patients are treated for a longerperiod, e.g. 3 months to 1 year or even 1 to 6 years, with a combinationaccording to the invention and are compared with patients who have beentreated with other antidiabetic and/or antiobesity medicaments. There isevidence of therapeutic success compared with other treatments if no oronly a slight increase in the fasting glucose and/or HbA1c value isobserved. Further evidence of therapeutic success is obtained if asignificantly smaller percentage of the patients treated with acombination according to the invention, compared with patients who havereceived another treatment, undergo a deterioration in the glucosemetabolic position (e.g. an increase in the HbA1c value to >6.5% or >7%)to the point where treatment with an (additional) oral antidiabeticmedicament or with insulin or with an insulin analogue is indicated.

Example 5 Treatment of Insulin Resistance

In clinical studies running for different lengths of time (e.g. 2 weeksto 12 months) the success of the treatment is checked using ahyperinsulinaemic euglycaemic glucose clamp study. A significant rise inthe glucose infusion rate at the end of the study, compared with theinitial value or compared with a placebo group, or a group given adifferent therapy, proves the efficacy of a treatment according to theinvention in the treatment of insulin resistance.

Example 6 Treatment of Hyperglycaemia

In clinical studies running for different lengths of time (e.g. 1 day to24 months) the success of the treatment in patients with hyperglycaemiais checked by determining the fasting glucose or non-fasting glucose(e.g. after a meal or a loading test with oGTT or a defined meal). Asignificant fall in these glucose values during or at the end of thestudy, compared with the initial value or compared with a placebo group,or a group given a different therapy, proves the efficacy of acombination treatment according to the invention in the treatment ofhyperglycaemia.

Example 7 Effect of Empagliflozin Versus Glimepiride on Beta-CellFunction

In a Phase III study the effects of empagliflozin and the SU glimepirideas second-line therapy are compared in patients with T2DM inadequatelycontrolled with metformin immediate release (IR) and diet/exercise.

After a 2-week placebo run-in, patients are randomized to receiveempagliflozin 25 mg once daily (qd) or glimepiride 1-4 mg qddouble-blind for 104 weeks, in addition to metformin IR. Patients whoparticipate in the initial 104-weeks randomization period will beeligible for a 104-week double-blind extension.

The primary endpoint is change from baseline in HbA_(1c). Secondaryendpoints are change from baseline in body weight, the incidence ofconfirmed hypoglycemia, and changes in systolic and diastolic bloodpressure. Exploratory endpoints include change from baseline in FPG, theproportion of patients achieving HbA_(1c)<7%, and effects on variousbiomarkers of beta-cell function including insulin, C-peptide, HOMA-Band proinsulin to insulin ratio, first and second phase insulinsecretion after a meal tolerance test.

In addition, primary, secondary and exploratory endpoints are evaluatedin a sub-group of patients with Latent Autoimmune Diabetes in Adulthood(LADA), identified by the presence at baseline of autoantibodies againstinsulin, islet cell cytoplasm, glutamic acid decarboxylase 65 or theintracytoplasmic domain of the tyrosine phosphatase-like protein IA-2.

Example 8 Effect of Empagliflozin Arterial Stiffness

Blood pressure, arterial stiffness, heart rate variability (HRV) andcirculating adrenergic mediators were measured during clamped euglycemiaand hyperglycemia in 40 normotensive patients with T1D. Studies wererepeated after 8 weeks of empagliflozin (25 mg daily).

Augmentation index (Alx) for the radial and carotid arteries as well asa derived aortic Alx and carotid, radial and femoral pulse wavevelocities (PWV) are measured for assessment of arterial stiffness usinga SphygmoCor® System (AtCor Medical Inc., Itasca, Ill.). During clampedeuglycemic conditions, empagliflozin reduced systolic blood pressure(111±9 to 109±9 mmHg, p=0.0187), and augmentation indices at the radial(−52±16 to −57±17%, p<0.0001), carotid (+1.3±17.0 to −5.7±17.0%,p<0.0001) and aortic positions (+0.1±13.4 to −6.2±14.3%, p<0.0001)declined. Similar effects on arterial stiffness were observed duringclamped hyperglycemia; however, blood pressure effects were notsignificant. Carotid-radial pulse wave velocity decreased significantlyunder both glycemic conditions (p≦0.0001), while declines incarotid-femoral pulse wave velocity were only significant during clampedhyperglycemia (5.7±1.1 to 5.2±0.9 m/s, p=0.0017). HRV, plasmanoradrenaline and adrenaline remained unchanged under both glycemicconditions.

This shows that empagliflozin reduces arterial stiffness in patientswith uncomplicated T1D.

Example of Pharmaceutical Composition and Dosage Form

The following example of solid pharmaceutical compositions and dosageforms for oral administration serves to illustrate the present inventionmore fully without restricting it to the contents of the example.Further examples of compositions and dosage forms for oraladministration, are described in WO 2010/092126. The term “activesubstance” denotes empagliflozin according to this invention, especiallyits crystalline form as described in WO 2006/117359 and WO 2011/039107.

Tablets containing 2.5 mg, 5 mg, 10 mg, 25 mg, 50 mg of active substance

2.5 mg/ 5 mg/ 10 mg/ 25 mg/ 50 mg/ Active substance per tablet pertablet per tablet per tablet per tablet Wet granulation active substance2.5000 5.000 10.00 25.00 50.00 Lactose Monohydrate 40.6250 81.250 162.50113.00 226.00 Microcrystalline Cellulose 12.5000 25.000 50.00 40.0080.00 Hydroxypropyl Cellulose 1.8750 3.750 7.50 6.00 12.00Croscarmellose Sodium 1.2500 2.500 5.00 4.00 8.00 Purified Water q.s.q.s. q.s. q.s. q.s. Dry Adds Microcrystalline Cellulose 3.1250 6.25012.50 10.00 20.00 Colloidal silicon dioxide 0.3125 0.625 1.25 1.00 2.00Magnesium stearate 0.3125 0.625 1.25 1.00 2.00 Total core 62.5000125.000 250.00 200.00 400.00 Film Coating Film coating system 2.50004.000 7.00 6.00 9.00 Purified Water q.s. q.s. q.s. q.s. q.s. Total65.000 129.000 257.00 206.00 409.00

Details regarding the manufacture of the tablets, the activepharmaceutical ingredient, the excipients and the film coating systemare described in WO 2010/092126, in particular in the Examples 5 and 6,which hereby is incorporated herein in its entirety.

1) A method for treating and/or preventing oxidative stress, collagendeposition, vessel wall thickening, vascular stress and/or endothelialdysfunction comprising administering empagliflozin, optionally incombination with one or more other therapeutic substances, to a patientin need thereof. 2) The method of claim 1, wherein the patient is anon-diabetic patient or a type 2 or type 1 diabetes mellitus patient. 3)The method of claim 1, wherein the method is for treating and/orpreventing endothelial dysfunction in a type 2 or type 1 diabetesmellitus patient. 4) A method of treating type 2 or type 1 diabetesmellitus in a patient with or at risk of oxidative stress, vascularstress and/or endothelial dysfunction, or diseases or conditions relatedor associated therewith, said method comprising administeringempagliflozin, optionally in combination with one or more othertherapeutic substances, to the patient. 5) The method according to claim4, wherein said patient has or is at risk of a cardiovascular disease.6) The method according to claim 4, wherein the patient has or is atrisk of a cardiovascular disease selected from myocardial infarction,stroke, peripheral arterial occlusive disease. 7) A method ofpreventing, reducing the risk of or delaying the occurrence of acardiovascular event in a patient with type 2 or type 1 diabetesmellitus or with pre-diabetes, said method comprising administeringempagliflozin, optionally in combination with one or more othertherapeutic substances, to the patient. 8) The method according to claim7, wherein said patient has or is at risk of a cardiovascular disease.9) The method according to claim 7, wherein the patient has or is atrisk of a cardiovascular disease selected from myocardial infarction,stroke, peripheral arterial occlusive disease. 10) A method of treatinga metabolic disorder and preventing, reducing the risk of or delayingthe occurrence of a cardiovascular event in a patient comprisingadministering empagliflozin, optionally in combination with one or moreother therapeutic substances, to the patient. 11) The method accoding toclaim 10, wherein said metabolic disorder is type 2 or type 1 diabetesmellitus or pre-diabetes. 12) The method according to claim 10, whereinsaid cardiovascular event is selected from cardiovascular death,non-fatal myocardial infarction, non-fatal stroke, hospitalisation forunstable angina pectoris and heart failure requiring hospitalization 13)The method according to claim 10, wherein said cardiovascular death isdue to fatal myocardial infarction or fatal stroke. 14) The methodaccording to claim 10, wherein the patient is a patient with type 2 ortype 1 diabetes mellitus or with pre-diabetes with one or morecardiovascular risk factors selected from A), B), C) and D): A) previousor existing vascular disease selected from myocardial infarction,coronary artery disease, percutaneous coronary intervention, coronaryartery by-pass grafting, ischemic or hemorrhagic stroke, congestiveheart failure, and peripheral occlusive arterial disease, B) advancedage >/=60-70 years, and C) one or more cardiovascular risk factorsselected from advanced type 2 diabetes mellitus >10 years duration,hypertension, current daily cigarette smoking, dyslipidemia, obesity,age >/=40, metabolic syndrome, hyperinsulinemia or insulin resistance,and hyperuricemia, erectile dysfunction, polycystic ovary syndrome,sleep apnea, or family history of vascular disease or cardiomyopathy infirst-degree relative; D) one or more of the following: confirmedhistory of myocardial infarction, unstable angina with documentedmultivessel coronary disease or positive stress test, multivesselPercutaneous Coronary Intervention, multivessel Coronary Artery By-passGrafting (CABG), history of ischemic or hemorrhagic stroke, peripheralocclusive arterial disease. 15) A method of treatment comprising: a)identifying a patient in need of treatment for type 2 or type 1 diabetesmellitus and with or at risk of cardiovascular disease; and b)administering empagliflozin to said patient. 16) The method according toclaim 15, wherein the patient has or is at risk of a cardiovasculardisease selected from myocardial infarction, stroke, peripheral arterialocclusive diasease. 17) The method according to claim 15, wherein thepatient is a patient with type 2 or type 1 diabetes mellitus or withpre-diabetes with one or more cardiovascular risk factors selected fromA), B), C) and D): A) previous or existing vascular disease selectedfrom myocardial infarction, coronary artery disease, percutaneouscoronary intervention, coronary artery by-pass grafting, ischemic orhemorrhagic stroke, congestive heart failure, and peripheral occlusivearterial disease, B) advanced age >/=60-70 years, and C) one or morecardiovascular risk factors selected from advanced type 2 diabetesmellitus >10 years duration, hypertension, current daily cigarettesmoking, dyslipidemia, obesity, age >/=40, metabolic syndrome,hyperinsulinemia or insulin resistance, and hyperuricemia, erectiledysfunction, polycystic ovary syndrome, sleep apnea, or family historyof vascular disease or cardiomyopathy in first-degree relative; D) oneor more of the following: confirmed history of myocardial infarction,unstable angina with documented multivessel coronary disease or positivestress test, multivessel Percutaneous Coronary Intervention, multivesselCoronary Artery By-pass Grafting (CABG), history of ischemic orhemorrhagic stroke, peripheral occlusive arterial disease. 18) A methodfor preventing, slowing, delaying or treating the degeneration ofpancreatic beta cells and/or the decline of the functionality ofpancreatic beta cells and/or for improving and/or restoring and/orstimulating and/or protecting the functionality of pancreatic beta cellsand/or restoring the functionality of pancreatic insulin secretion in apatient having latent autoimmune diabetes in adults (LADA) comprisingadministering empagliflozin, optionally in combination with one or moreother therapeutic substances, to the patient. 19) The method accordingto claim 18, wherein the patient having LADA is a patient in whom one ormore autoantibodies selected from GAD (GAD-65, anti-GAD), ICA, IA-2A,ZnT8 (anti-ZnT8) and IAA are present. 20) A method for preservingpancreatic beta cells and/or their function in a patient having latentautoimmune diabetes in adults (LADA) comprising administeringempagliflozin, optionally in combination with one or more othertherapeutic substances, to the patient. 21) The method according toclaim 20, wherein the patient having LADA is a patient in whom one ormore autoantibodies selected from GAD (GAD-65, anti-GAD), ICA, IA-2A,ZnT8 (anti-ZnT8) and IAA are present. 22) A method for treating and/orpreventing LADA (latent autoimmune diabetes of adults) in a patient, themethod comprising administering empagliflozin, optionally in combinationwith one or more other therapeutic substances, to the patient. 23) Themethod according to claim 22, wherein the patient having LADA is apatient in whom one or more autoantibodies selected from GAD (GAD-65,anti-GAD), ICA, IA-2A, ZnT8 (anti-ZnT8) and IAA are present. 24) Amethod for reducing arterial stiffness in a patient comprisingadministering empagliflozin to the patient, optionally in combinationwith one or more other therapeutic substances, to the patient. 25) Themethod according to claim 1, wherein the one or more other therapeuticsubstances are selected from other antidiabetic substances. 26) Themethod according to claim 1, further comprising administeringempagliflozin in combination with metformin, with linagliptin or withmetformin and linagliptin. 27) The method according to claim 1, whereinempagliflozin is administered orally in a total daily amount of 10 mg or25 mg. 28) The method according to claim 1, wherein empagliflozin isadministered as a pharmaceutical composition comprising 10 mg or 25 mgof empagliflozin.